2-(2-phenyl-1,1,2,2-tetrafluoroethyl)-benzylamines

ABSTRACT

NEW FLUORO DERIVATIVES OF ARALKYLAMINE COMPOUNDS, PARTICULARLY 2-(2-PHENYL-1,1,2,2-TETRAFLUOROETHYL) BENZYLAMINE AS WELL AS THE N-ALKYL AND THE N,N-DISLKYL DERIVATIVES THEROF ARE PREPARED BY REACTION OF 2-BROMOBENZONITRILE WITH BENZYLMAGNESIUM CHLORIDE TO PRODUCE 2&#39;&#39;-BROMO-2PHENYLACETOPHENONE; OXIDATION OF SAID ACETOPHENONE WITH SELENOUS ACID TO PRODUCE 2-BROMOBENZIL; CONVERSION OF THE BENZIL COMPOUND BY TREATMENT WITH SULFUR TETRAFLUORIDE TO THE CORRESPONDING 2-BROMO-A,A,A&#39;&#39;,A2-TETRAFLUOROBENZYL; FOLLOWED BY REACTION OF THE 2-BROMOBIBENZYL COMPOUND WITH A METAL CYANIDE TO PRODUCE THE CORRESPONDING 2-(2-PHENYL1,1,2,2-TETRAFLUOROETHYL) BENZONITRILE. THIS NITRILE COMPOUND IN THEN CORRESPONDING BENZYLAMINE, WHICH IS THEN PRODUCE THE CORRESPONDING BENZYLAMINE, WHICH IS THEN CONVERTED, IF DESIRED, TO THE N-ALKYL AND/OR N,N-DIALKYL 2-(2-PHENYL-1,1,2,2-TETRAFLUOROETHYL) BENZYLAMINE. ALTERNATIVELY, THE NITRILE OR THE PRECURSOR BROMOBIBENZYL CAN BE CONVERTED BY GRINARD REACTIONS TO THE CORRESPONDING A-ALKYL OR A,A-DIALKYLBENZYLAMINE WHICH CAN THEN BE CONVERTED IF DESIRED TO THE CORRESPONDING N-ALKYL AND/OR N,NDIALKYL SUBSTITUTED BENZYLAMINE COMPOUND. THE PHENYLTETRAFLUOROETHYLBENZYLMINE AS WELL AS ITS N-ALKYL AND N, N-DIALKYL DERIVATIVES ARE ACTIVE AS ANTIARRHYTHMIC AGENTS.

i 3,812,177 '-PHENYL -1',1,2,2-TETRAFLUOROETHYL)- -"BENZYLAMINES Edward-L; En'gelhardt, Gwynedd Valley, and Marcia E. LChristy, Perkasie, Pa., assignors to-Merck & Co.,In'c., -,Rahway,.N-J.,, i No .;Dravying.,- Continuation-in-part of application Ser. No. 799,945, Feb- 2, l 969, which is a continuation-in-part ,Qf applications er. No. 712,616, Mar. 13, 1968, both now'abandp' @This application Dec. 28, 1 970, Ser. "No.102,'130 Q A Int. Cl. C07c 87/28 UiStCll'QGll- -ESOIJI 7 Claims ABSTRACT OF THE DISCLOSURE New fluoro derivatives of aralkylamine compounds, particularly 2-(2-pheny1;1,1,2,2-tetraflu0roethyl)benzylamine as well as the N-alkyl/and the N,N-dialkyl derivatives thereof are prepared by reaction of 2-bromobenzonitrile with benzylmagnesium chloride to produce 2-bromo-2- 'phenylacetophenone; oxidation of said acetophenone with selenous acid to produce 2-bromobenzil; conversion of the benzil compound by treatment with sulfur tetrafluoride to the corresponding 2- bromo-u,a,a',a -tetrafluorobenzyl; followed by reaction of the 2-bromobibenzyl compound with a metal cyanide to produce the corresponding 2-(2-phenyl- 1,1,2,2 tetrafiuoroethyl)benzonitrile. This nitrile compound is then reduced with lithium aluminum hydride to produce the corresponding benzylamine, which is then converted, if desiredflto theN- alkyland/or N,N-dialkyl 2- (Z-phenyl-1,1,2,2 tetrafluoroethyl) benzylamine. Alternatively, the nitrile or the precursor bromobibenzyl can be converted by Grignard reactions to the corresponding et 'alkyl or u,a-dialkylbeuzylamin'e which can then be converted if desired to the corresponding N-alkyl and/ or N,N- dialkyl substituted benzylamine compound. The phenyltetrafluoroethylbenzylamine as well as its N-alkyl and N, N dialkyl derivatives are active as antiarrhythmic agents.

This application-is a continuation-in-part of application Ser. No. 7 99,94S3fi1ed Feb. 2, 1969, and nowabandoned which inpturn is a continuation-in-part of application Ser. No. 712,616, filed Mar. 13, 1968 and now abandoned.

This invention relates to fluoro derivatives of aralkylamine compounds. More specifically, it relates to perfluoroallrylaralkylamines containing an additional homocyclie eteroeyclictring and the corresponding N-substitutedderivatives such as the N-alkyl and N,N -dialkyl derivatives thereof. v

This inyentiongalso relates to the novel processes and the novel" intermediates utilized in theproduction of new perfluoroalkylaralkylamines, to pharmaceutical formulations of the new'aralkylamines and to methods of treating or preventing cardiac arrhythmias using the novel compounds a" d/of'pharrnaceutical formulations thereof, describedhereinafter: 7 i J in 1 it The new compou of our invention are terminally disubstituted,perfluoroallianei compounds in which oneof the two terminal substituents is an aromatic ring havingat least on e of its hydrogens replaced by a straight or brarich ed'cliain aminoalky'l "adical mm amino heter'ocyclic radical and in which t'h'e- 9 erterminal'substituent is a homo: lietero'cyclic*rin'g"selected from aryl, substituted aryl, hetr o'cyclic and substituted heterocyclic substituents.

7 3,812,177 Patented May 21, 1974 c ce The compounds of our invention are represented structurally as follows:

F2)nA I in which n is an integer varying from 2 to 4 inclusive; A is a substituted or unsubstituted homocyclic or heterocyclic ring of from 5 to 6 atoms, such as an aromatic ring a heteroaromatic ring or a partially or completely reduced aromatic or heteroaromatic ring;. and B is an amino subsituted straight or branched chain aliphatic or heterocyclic side chain containing from ,1 to 8 carbon atoms which is connected to the benzenoid ring by one or more carboncarbon bonds.

A preferred class of compounds of our invention are the aminoalkylarylperfiuoroalkanes represented structurally by the formula in which n is an integer varying from 2 to 4 inclusive; m is an integer varying from 1 to 4 inclusive; one or more of the methylene (CH hydrogens may be replaced by a lower alkyl (1-4 carbon atoms) substituent; R and R5, are either similar or dissimilar and are either hydrogen, alkyl (preferably of from 1 to 6 carbon atoms), alkenyl or alkynyl, and can be joined together or alternatively may be linked to the aromatic ring or to one of the methylene substituents linking the aromatic ring and the amine radical to form a heterocyclic ring of from 5 to 6 atoms such as imidazolinyl, piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or loweralkyl piperazinyl and A is aryl, especially phenyl or substituted phenyl, heterocyclio aromatic or a; partially or completely reduced derivative thereof. V

p Also included within the scope of our invention are derivatives of compounds having the above formula in which one or more of the aryl heterocyclic rings or one of the reduced derivatives is further substituted. A preferred group of such compounds includes derivatives in which one or more of the hydrogens of the phenyl ring and/or one or more of the hydrogens of the ring represented by A is replaced by substituents selected from the group consisting of hydrogen, an alkyl group having up to'6 carbon atoms, an alkenyl group having up to 6 carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, a phenyl or a substituted phenyl radical, an acyl group having up to 4 carbon atoms, a perfluoroacyl group having up to 4 carbon atoms, amino, an alkylamino group having up to a 4, carbon atoms, an alkylaminoalkyl group havingup'to 8 carbon atoms, a dialkylamino group havto '8 carbon atoms, a dialkylaminoalkyl group up to 10 carbon atoms, an acylamino group having up to}; carbon atoms, a perfluoroacylamino group having up to 4'carbon atoms, an alkylsulfonylamino group propionic acid, lactic acid,

having up to 4 carbon atoms, halogen (fluorine, chlorine, bromine, or iodine), hydroxyl, an alkoxyl group having up to 4 carbon atoms, a perfluoroalkoxy group having up to 4 carbon atoms, cyano, carboxy, carbamoyl, an alkylcarbamoyl group having up to 5 carbon atoms, a dialkylcarbamoyl group having up to 9 carbon atoms, a carbalkoXy group having up to 6 carbon atoms, mercapto, an alkylmercapto group having up to 4 carbon atoms, a perfluoroalkylmercapto group having up to 4 carbon atoms, an alkylsulfonyl group having up to 4 carbon atoms, .a perfluoroalkylsulfonyl group having up to carbon atoms, sulfamoyl, an alkylsulfamoyl group having up to 4 carbon atoms, or a dialkylsulfamoyl group having up to 8 carbon atoms. More than one of these substituents may be on each ring.

An especially preferred group: of compounds included within the scope of our invention is represented by the formula CFr-C Fa- -CHzN or derivatives of these compounds in which one or more of the methylene (CH hydrogens is replaced by a lower alkyl (of from 1 to 4 carbon atoms) substituent, in which R and R are either hydrogen, alkyl (preferably of from 1 to 6 carbon atoms), alkenyl, alkynyl, and can be joined together through an atom of nitrogen, oxygen or sulfur to form a heterocyclic ring of from 5-6 atoms (such as l-piperidyl, l-pyrrolidinyl, 4-morpholinyl, 4-thiomorpholinyl or 1-loweralkyl-4-piperazinyl).

Illustrative of the compounds included within the scope of the invention are 2-(2-phenyl-1,1,2,2-tetrafluoroethyl) benzylamine, a methyl 2 (Z-phenyl-l,1,2,2-tetrafluoroethyDbenzylamine, ot,oz dimethyl 4 (2 phenyl-1,1,2,2- tetrafiuoroethyl) benzylamine, a-methyl-4- (2-pheny1-1,1,2, 2-tetrafluoroethyl)benzylamine, the corresponding secondary amines as, for example, the N-methyl, N-ethyl, N-propyl, N-allyl, N-propargyl, N-isopropyl, N-butyl, N- t-butyl, N-amyl and the N-acyl derivatives thereof, as well as the corresponding N,N-disubstituted derivatives, especially the N,N-dialkyl derivatives, thereof.

The compounds represented above, in either their free base or salt form, possess useful pharmacological prop erties. In particular, they have been found to possess antiarrhythmic activity. It has been found that the administration of compounds of the present invention, depicted in the above formula, results in the prevention of arrhythmia in animals under conditions which ordinarily cause the development of arrhythmia in the animal 1007 of the time.

A It has further been found that administration of the compounds of the present invention will arrest an existing arrhythmia in the animal being treated and cause a resumption of normal cardiac rhythm. As anti-arrhythmic agents, these compounds may be administered orally or parenterally. The formulations for administration may be prepared in conventional manner, employing conven tional pharmaceutical carriers and excipients.

The non-toxic acid addition salts useful as components in the compositions provided by the present invention are salts formed by the reaction of an equivalent amount of the amine compounds of the above formula and an acid which is pharmacologically acceptable in the intended doses. Salts of the above compound which are useful are salts of the amine with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, isethionic a id, furnaric acid, acetic acid,

gluconic acid, maleic acid, succiriic acid, tartaric acid,"arl'd' the like. Thesalrs' ofthe compounds of this invention are prepared for convenience in preparing pharmaceutical formulations. The pharmacological action of the salts is considered to be the same as the chemically equivalent quantity of the bases.

The daily doses are based on the total body weight of the test animal and vary between about 1.00 and 100.00 mg./kg. Thus, a unit dose based on four-times-a-day administration is between 2.5 mg. and 250 mg. for a 10 kg. dog, and a total daily dose for a 10 kg. dog would vary between about 10 mg.- and 1,000 mg. For larger animals,- proportional dosages are employed; based on the weight of the animal. Suitable dosage forms provided for the administration of the compositions used in the method of the invention are tablets, capsules (which may be suitably formulated for either immediate or sustained release), syrups, 'elixirs, parenteral solutions, and the like. These dosage forms preferably contain ,per unit one or more multiples of'the desired dosage unit in combination with the pharmaceutically acceptable diluent or carrier required for preparing the dosage unit. I v i The compounds represented by the above structural formulas may be prepared as illustrated below.

FLOW SHEET I *This step may include a homologation procedure involving conversion of the cya'uo substituent through the conventional sequence of hydrolysis to the corresponding carhoxyl derivative, lithium aluminum hydride reduction to 'CH2OH, conversion to CHQX (where X=halogeu or s'ulfonyloxy) and treatment with cyanide ion to produce the next higher:- homolog.

wherein I R is hydrogen or lower alkyl (preferably of from 1-5 carbon atoms) or amino substituted; lower alkyl; 7 R and R can be similar or dissimilar and are either hydrogen, alkyl (preferably of from 1-6 carbon atoms),

aralkyl (preferably benzyl or phenethyl), alkenyl, alkynyl, and can be joined together or with one of the methylene carbons linking the amine substituent and the phenyl ring or through an atom of nitrogen, oxygen or sulfur to'form a heterocyclic-fing of from 5-6 atoms (such as imidazolinyl, piperidyl, pyrrolidinyl,

morpholinyl, thiomorpholinyl or loweralkyl piper azinyl);

X and X are selected from the group consisting of hydrogen, halogen (chlorine or fluorine), alkyl (preferably of from l-6 carbon atoms), alkoxy, (preferably of from 1-5 carbon atoms), perfiuoroalkyl (e.g., trifluoromethyl), alkylmercapto (preferably of from 1-6 carbon atoms), alkylsulfonyl (preferably of from 1-6 carbon atoms), and dialkylsulfamoyl (preferably of from 2-8 carbon atoms);

Hal is a halogen selected from the group consisting of bromine or iodine; i

n is an integer selected from the group consisting of 2 and 3;

m is an'integer selected from the group consisting of 1 to 4 inclusive; Alk is alkyl (preferably lower alkyl of from 1-6 carbon atoms); and

A is an aromatic ring such as phenyl, 'a cycloaliphatic ring, a heterocyclicaromatic ring of 5 or 6 atoms or a partially reduced or completely reduced heterocyclic ring including preferably pyridine, pyrimidine, thiazole, thiophene, imidazole, oxazole and partially or completely hydrogenated derivatives thereof. In accordance with the process of our invention, the dior triketone Compound I is treated with sulfur tetrafluoride to convert the diketoor. triketo compound to the corresponding diarylperfluoroalkyl compound as, forbromophenyl) 1,1,2,2,3,3 hexafluoro-3-phenylpropane.

This conversion to the perfiuoro compound is preferably carried out at elevated temperatures bymixing the dior triketone with an excess of sulfur tetrafluoride and catalytic amounts of a Lewis acid such ashydrogen fluoride, boron trifluoride and the like.

Thhe sulfur tetrafluoride employed in the reaction is either purified prior to addition to the reaction mixture by shaking in contact with a small amount of mercury or by adding the mercury directly to the reaction mixture.

The amount of mercury employed is not critical but it is preferred to employ at least about 1 gram of mercury/ 100 g. of sulfur tetrafiuoride to remove undesirable contaminants such as sulfur chloride. Preferably, the sulfur tetrafluoride is treated in situ by the direct addition of mercury to the mixture containing sulfur tetrafiuoride and dior triketone.

The temperature of the reaction mixture is not critical but is preferably maintained between 50 and 200 C. The perfiuoro compound is readily obtained from the re action mixture by extraction with solvents such as benzene, toluene, methylene chloride, chloroform, or the like, and evaporation of the solvent to yield the compound as a residual solid. I i

The thus-obtained phenylperfluoroalkylbromo benzene is converted into the correspondingly substituted ben: zom'trile by reaction of the substituted compound with a metal cyanide such as cuprous cyanide and suitable anhydrous nonhydroxylic solvents .such as. acetonitrile, dimethylformamide, quinoline orfpyridine to produce the corresponding benzonitrile. The preferred solvent is quinoline containing a small amount of ,dimethylformamide. The temperature at which the reaction'is carried out is not critical but itis preferred "to employ elevated temperatures in'the rangeof 100-200 C. The desired temuct is readily recovered employing conventional techniques to remove the metal saltswhich precipitate from the reaction mixture, followed b y filtration, evaporation of the solvent, if desired, followedby crystallization;

' The thus obtained phenylperfluoroalkylbenzonitrile is then reduced'to produce the corresponding benzylamine, e.g. 2-(2-phenyl-1,1,2,2-tetrafiuoroethyl) or 4-(3-phenyll,1,2,2,3,3-hexafiuoropropyl)benzylamine. The reduction is readily effected by contacting the benzonitrile compound with lithium aluminum hydride in the presence of a suitable inert organic solvent, such as tetrahydrofuran, ether or other solvents conventionally employed with lithium aluminum hydride. Preferably, this reduction is carried out in the presence of aluminum chloride and an ether compatible with aluminum chloride as a solvent. The temperature at which the reduction is carried out is not critical but it is preferred to employ ambient temperatures and a range of from 0-50 C. is satisfactory. The resulting benzylamine compound is readily recovered employing conventional techniques.

In preparing higher homologs of the benzylamine compound, the intermediate phenylperfiuoroalkylaryl nitrile is converted using conventional reaction methods to produce the desired compounds. Thus, the intermediate phenylperfiuoroalkylbenzonitrile is hydrolyzed to the corresponding benzoic acid. The thus-obtained acid is then reduced using lithium aluminum hydride to produce the corresponding benzyl alcohol which is recovered in accordance with conventional procedures and treated with a hydrogen halide such as aqueous hydrogen bromide to produce the corresponding benzyl halide. The thus-obtained product is purified using conventional techniques and subjected to treatment with potassium cyanide thereby completing the conversion of the starting benzonitrile to the next higher homolog, the phenylperfiuoroalkyl phenylacetonitrile.

The corresponding N (phenylperfiuoroalkylbenzyl) formamide (V) or higher homologs thereof in which R is hydrogen, is prepared by formylation of, the aralkylamine e.g. benzylamine compound (IV) employing conventional conditions and reagents such as formic acid or esters thereof for this purpose. The resulting formamide derivative can be recovered in conventional manner. The N,N-dimethylamine (VI), wherein R and R each repre sent methyl, is readily prepared by the treatment of the primary amine compound (V) with formaldehyde and formic acid in accordance with the known Eschweiler- Clarke modification of the Leuckart Reaction. Recovery of the N,N-dimethylamine is accomplished in conventional manner. The N-methylaralkylamine, e.g. the N- methylbenzylamine, represented by (VII) wherein All: is methyl, may be prepared by either reduction of the corresponding N-(phenylperfluoroalkylbenzyl)formamide (V) or by mono-dealkylation of the corresponding N,N-dimethylamine (VI) wherein 'R and R each represent methyl. Reduction of the formamidomethyl derivative is effected utilizing lithium aluminum hydride under the conditions set forth above for carrying out the reduction of the corresponding benzonitrile (HI). Similarly, dealkylation of the N,N-dimethylamine (VI) can be effected in known manner such as by treatment with cyanogen bromide followed by hydrolysis of the intermediate cyanamide or by treatment with a haloformate followed by hydrolysis of the resulting urethane intermediate. In each instance, the desired compound can be recovered employing conventional techniques.

The N-loweralkylamines and the N,N diloweralkylamines corresponding to compounds (VII) and (VI), respectively, are likewise prepared from the corresponding primary amine (IV) by analogous reactions. Thus, the primary amine (IV) is treated with a lower aliphatic acid halide or anhydride of from 2-5 carbon atoms, e.g., acetyl chloride, acetic anhydride, propionyl chloride, butyryl chloride or valeryl chloride to produce the N- alkanoyl amide corresponding to (V) as, for example, the N-acetyl, N-propionyl, N-butyryl or N-valeryl amide. The thus-obtained amide is reduced to the corresponding N-loweralkyl benzylamine compound (VI) by reduction in the manner described for" the corresponding benzonitrile compound v(III), i.e., by reduction with lithium aluminum hydride. The secondary amine compounds (VII) produced in this manner are theN-loweralkyl derivatives of 2-(phenylperfiuoroalkyl)benzylamines as, for example, the N-ethyl, N-propyl, N-butyl and the N-amyl derivatives. The corresponding tertiary amines (VI), the N,N-diloweralkyl derivatives, are prepared from the secondary amines by repeating the process employed in the preparation of the secondary amines. Thus, the amides of the secondary amines are prepared and reduced with lithium aluminum hydride to produce the corresponding tertiary amines as, for example, the corresponding N,N- diethyl, N-ethyl-N-methyl, N,N-dipropyl, N,N-dibutyl and the N,N-diamyl derivatives of substituted and unsubstituted phenylperfluoroalkyl benzylamine.

In accordance with an alternative process for the preparation of the compounds of formula (VI), wherein FLOW SHEET H Alternative process for primary, secondary, or tertiary benzylamine products corresponding to (IV), (VI) or (CH2) rx x' Hal s II 9) n v x x CHaHal 11 Ra IIE wherein Hal, n, R R X and X have the significance previously indicated.

Thus, the bromo or iodo substituted diaryl perfluoroalkyl compound (II) is treated with magnesium under anhydrous conditions to form the Grignard reagent (IIA) which, in turn, is treated with carbon dioxide, followed by acidic hydrolysis to produce the corresponding carboxylic acid (IIB) wherein the bromo or iodo substituent is replaced by a carboxyl group. The thus-obtained acid is then reduced using lithium aluminum hydride to produce the corresponding benzyl alcohol (IIC) which is recovered in accordance with conventional procedures and treated with an acid halide such as thionyl chloride, thionyl bromide, and the like, to produce the corresponding benzyl halide compound (IID) which, on reaction with ammonia or an amine, produces the corresponding primary, secondary or tertiary amine (RE) which is recovered employing conventional techniques. In this manner, there is produced in addition to the N-alkyl and N,N-dialkyl derivatives of the substituted and unsubstituted phenylperfluoroalkylbenzylamines or higher homologs thereof enumerated hereinabove, the corresponding compounds in which the amine nitrogen forms a. part of a heterocyclic ring such as a piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl or l-loweralkyl- 4-piperazinyl ring. a

The benzyl halide (IID) is alternatively prepared from alkylated tetrafluorobibenzyl compounds, e.g. 2,3-dimethyl-u, a,a',a'-tetrafiuorobibenzyl by selective bromination of the alkyl substituent using the appropriate molar amount of an N-bromoimide, e.g. N-bromo succinimide, to produce the desired substituted benzyl bromide. There can be one or more alkyl substituents present in the aromatic ring and by selection of the proper molar amount of the N-bromoamide the compound produced will have one or more of the alkyl substituents substituted by bromine with resultant production of the desired benzyl bromide compound. The bromine substituent is then replaced by the desiredamine function by any of a number of known methods for converting benzyl bromides to the corresponding benzyl amine or substituted amine. Thus, the obtained benzyl bromide compound is contacted withhexamethylene tetramine to produce the corresponding hexaminium bromide compound which on reaction with concentrated hydrochloric acid yields the desired benzyl amine. Alternately, the benzyl bromide compound is reacted with potassium phthalimide to produce the corresponding phthalimide derivative which on acid hydrolysis or reaction with hydrazine yields the desired benzylamine.

The perfluoroalkylaralkylamines in which the amine nitrogenis attached to a branched chain aliphatic side chain are readily prepared by the reaction of the appropriately substituted nitrile III with a lower alkyl magnesium halide, e.g. methyl magnesium bromide, to produce an intermediate imine followed by lithium aluminum hydride reduction of the imine to produce the corresponding branched chain primary amine wherein the alkyl substituent is attached to the carbon immediately adjacent to the 'aminoxsubstitutent. For example, when 2-(oz,a,B,/3- tetrafluorophenethyl)benzonitrile is treated in turn with methyl magnesium bromide to produce the intermediate ketimine followed by reduction with lithium aluminum hydride, the product produced is a-methyl-2-(a,a,/3,fitetrafluorophenethyl)benzylamine. When the starting benzonitrile is replaced by the homologous 2-(ot,ot,}9,/3- tetrafluorophenethyl)phenylacetonitrile, the products obtained following ketimine formation with the appropriate Grignard reagent and lithium aluminum hydride reduction are respectively the a-methyl, u-ethyl, and a-propyl derivatives of 2-(a,a,[i, 3-tetrafluorophenethyl)phenethylamine.

- In an alternate method of producing such a-alkyl substituted benzylamines, the benzonitrile III is converted by reaction with a loweralkyl Grignard reagent, e.g., methyl, ethyl, propyl or butyl magnesium bromide, to the Grignard adduct followed by acidic hydrolysis to produce the 4' (a,a,fi,fi tetrafluorophenethyl) acetophenone compound. The acetophenone compound is then converted in conventional manner to the corresponding oxime which 'in turn is catalytically hydrogenated to produce the desired a-alkyl substituted benzylamine compound.

In addition to the OL'EllkYL-Z-(OL,Ot,fi,fl-ttIafll1OIOph6I1- ethyD-phenethylamine compounds, the corresponding, 'a,a-disubstituted, i.e., dialkyl compounds are prepared by processes starting from a bromo or iodo substituted diaryl per-fluoroal kyl compound II hereinabove in which Hal is bromo or iodine. The compounds prepared in accordance with the following processes are, for example, the a,ot-dimethyl, ot-diethyl, a,ot-dipropyl, a-methyl-otethyl, ot-methyl-a-propyl, a-ethyl-ot-propyl, a-methyl-otbutyl, and ot-methyl-a-isopropyl(a,a,;8, 3-tetrafluorophenethyl)benzylamine. The corresponding N-alkyl or N,N- dialkyl derivatives thereof, e.g., the Nmethyl, N-ethyl, N-propyl, N-butyl, N,N-dimethyl, N,N-diethyl, N,N-dipropyl, N-methyl-N-ethyl, N-methyl-N-propyl, N-methyl- N-butyl and N-ethyl-N-propyl derivatives are prepared by methods described in the preceding pages for converting the benzylamine into the corresponding N-alkyl or N,N-dilakyl derivatives.

In the process outlined below, for producing Br HA.

MgBr HA1 i-t- F F Ri-C-R:

n HA2 F' F V F F M;- atl. l l I F F F F 'm-o-h, rat-( PR3 IIA: l v I the a-dialkyl substituted benzylamine compounds, a 3 or 4 bromo substituted diaryl perfluoroalkyl compound is treated with magnesium nder anhydrous conditions to form the Grignard reagent HA which in turn is treated with an aliphatic ketone such as acetone, diethyl ketone, di-N-propyl ketone or a mixed ketone as, for example, methylethyl ketone, methyl-propyl ketone, methyl-butyl ketone, ethyl-propyl ketone and methyl-isopropyl ketone to produce after hydrolysis the corresponding benzyl alcohol HA containing alkyl substituents attached to the carbinol carbon of the benzyl alcohol. Alternatively, the 3- or 4'-perfluoroalkylphenyl substituted acetophenone is treated with a loweralkyl Grignard reagent to produce after hydrolysis the a,a-dialkyl benzyl alcohol. Alternately, Grignard reagent HA; is carbonated to produce after hydrolysis the corresponding benzoic acid. This acid is esterified and treated with a lower alkyl Grignard reagent to produce after hydrolysis the a,a-dialkylbenzyl alcohol. This tertiary alcohol is then employed in a Ritter reaction which involves treatment of the tertiary alcohol with an alkali metal cyanide in sulfuric acid or methane sulfonic acid with resultant production of the corresponding benzyl formamide compound HA which on acid hydrolysis produces the desired 0t,0t-dlalky1 substituted benzylamine compound.

The diand triketones utilized as starting materials in the described process are readily prepared from known materials. Thus, the diaryl diketo compounds are readily prepared by initially condensing the appropriately substituted bromobenzonitrile with a benzylmagnesium halide to produce the corresponding bromophenylbenzyl ketimine followed by hydrolysis under acid conditions to produce a bromo-substituted acetophenone compound.

Alternatively, the diaryl diketo compounds are prepared by initially condensing the appropriately substituted benzonitrile or a nitrile of an appropriately substituted heterocyclic compound with a benzylmagnesium halide containing an additional bromo substituent attached to the phenyl ring of the benzylmagnesium halide to produce the corresponding bromophenylbenzyl ketimine or the bromophenyl heterocyclic ketimine followed by hydrolysis under acid conditions to produce phenylacetophenone or phenacyl heterocyclic compound. As previously indicated, the heterocyclic portion of the molecule has a heterocyclic aromatic ring of 5 or 6 atoms selected from pyrimidine, thiazole, thiophene, imidazole and oxazole.

The thus-obtained bromophenylacetophenone or bromophenacyl heterocyclic compound is then treated with a mild oxidizing agent, such as selenous acid, to produce a bromo-substituted benzil-type compound. The oxidation reaction is carried out in an aqueous medium containing a solvent for the bromophenylacetophenone. The solvent is preferably one which is at least partially water-miscible. Typical examples are dioxane, acetic acid or lower aliphatic alcohols. The temperature at which the reaction is carried out is not critical but it is preferred to employ elevated temperatures in the range of about 50150 C. The desired product is readily recovered employing conventional techniques such as by extraction with water-immiscible solvents. Solvents including benzene, xylene, toluene and the like are preferred.

The foregoing conversion is outlined in the following flow sheet.

PLOW SHEET III Preparation of starting diketone 7 11 l R m t X form-GK or X-tiT -cm C1 Hal t t m t t a a X] or 0.

Hal

In the above formulas Hal, X and X have the significance previously indicated.

The corresponding diarylpropanetrione included in formula (I), of Flow Sheet I is prepared in accordance with the process of our invention as outlined in the following flow sheet. FLOW SHEET IV Preparation of starting triketone -C O OH; CHO i l Hal l CH=OH X It e v A Hal l X 00 (DH-(3H Br Br XI Hal l B i OAlk Hal I C C O CHIC O- X Hal l D 1E1 X C O(|3C 0 Br X,

Hal E in which Hal, Alk, X and X have the significance previ- .ously indicated.

Thus, an appropriately substituted benzaldehyde is condensed with a brorno or iodo substituted acetophenone in the presence of an acid or alkaline condensing agent to produce as a first intermediate a substituted benzal acetophenone (A) which is isolated in accordance with conventional procedures and treated in a suitable solvent with an equimolar amount of bromine to produce the corresponding benzal acetophenone dibromide (B) and is isolated by conventional procedures. The dibromide is then treated with an excess of an alkali metal alkoxide, such as sodium methoxide, to produce a loweralkyl enol ether of the corresponding dibenzoyl methane compound (C). The enol ether is then hydrolyzed under acidic conditions to produce the corresponding dibenzoyl methane compound (D). The dibenzoyl methane compound is then treated with at least two molecular equivalents of bromine to produce the corresponding dibenzoyldibromomethane compound (E). The dibromo compound is then treated with sodium acetate and glacial acetic acid to re place the brorno substituents with acetoxy substituents and the resulting compound is hydrolyzed with water to the desired diarylpropanetrione monohydrate compound (F), which is converted by heating under vacuum to efiect a dehydration and produce the desired propanetrione material utilized as starting material in the preparation of the perfluoroalkyl compounds of our invention (I).

When the starting benzaldehyde compound is replaced by a heterocyclic aldehyde such as thiophen-2-aldehyde the product obtained is a l-aryl-3-heterocyclic propanetrione compound.

The starting 2, 3 or 4-bromobenzonitriles or heterocyclic nitriles containing additional X substituents in the aromatic or heteroaromatic ring are either known compounds or may be prepared from the corresponding benzoic or heterocyclic carboxylic acids by conversion of the acid to the corresponding amide and dehydration of the amide to the desired nitrile. The substituted benzylmagnesium halide is also readily prepared from the corresponding benzyl halide using conventional synthetic procedures.

EXAMPLE 1 2'-bromo-2-phenylacetophenone A solution of 2-bromobenzonitrile, 12.0 g. (0.066 mole) in ml. of absolute ether is added dropwise to a stirred solution of benzylmagnesium chloride prepared from 0.42 g. (0.264 g. atom) of magnesium turnings and 33.42 g. (0.264 mole) of benzyl chloride in 140 ml. of absolute ether in a nitrogen atmosphere. The mixture is stirred at room temperature for 7 hours and allowed to stand overnight. After cooling in an ice-bath, the adduct is hydrolyzed by the dropwise addition of ml. of 0.5 M citric acid. The organic phase is separated and the aqueous phase re-extracted with several portions of cold benzene. The combinedorganic layers are extracted with about 10 ml. of ice-cold 6 N hydrochloric acid in several portions. After chilling the combined acid extracts in an ice-bath for several hours, the precipitate of 2-bromonltepx b n yl k m ne ro l de;is cq ls sdi wa sd with 15% ethanol in ether, then witli'absolute ether. After brief air-drying, the salt is recrystallized' from cold methanol-ether, M.P. 176-1818. C. -31 The ketimine hydrochloride;suspended in 25ml. of?) N hydrochlorictacid, .is fheated on. the steam-bath for il /{hours The product 'separates as an oil and is extracted into benzene. Evaporation of the washed and dried be'nz en'iflextract' leaves]? the yellow oily product, N --l.6050. i

, Anrzlysisr-Calcd. for C H BrO: C, 61.11; H, 4.03; 131, 29.04. Found: C,1-6l.17; H, 3.97; Br,"28.99.'

EXAMPLE 2 2-bromobenzil 2Gbromo-2-phenylacetophenone, 5.2 g. (0.0189 mole) 268g. (0.02081mo'le) ,ofselenous acid, 15 ml. of pdio'xane, 'and 3,6 mlgof water are stirred at reflux for 18 hours. The two ph ase supernatant solution is withdrawn and the'residual precipitate of selenium washed with benzene. The combined solution and washings are concentrated to a small volume under reduced pressure andthe residue is partitioned between benzene and Water. Evaporation of the washed and dried benzene extract under reduced pressure leaves the yellow oily product." Asam 1e is characterized by conversion to the'crystalline derivative, 2-phenyl-3- (-2-brornophenyl) -quinoiraline. 2-bro1nobenzil, 0.58 g. 002 rnole), and -phenyIenediamine, 0.24 g. (0.0022 mole), are heatedtorefluxing in ml. of absolute ethanol for 3 hours. Evaporation of the solvent under reduced pressure and crystallization of the residue from 95% ethanol gives crystalline product M.P. 131-1325 C. A sample for analysis melts at 133- ;1.34.5.?-C.- after repeated recrystallizations from 95% ethanol. r Analysis.Calcd. for C H BrN z C,..66.5.1; H, 3.63; N, 7.76. Found: C, 66.45;. H, 3.55; N, 7.63.

. E PL 1 2-bromo,-u,a,a,u'-tetrafiuorobibenzyl;-1,;, b omobenzil, 216 g. acne-mole together with 33 g f sulfur tetr'aiiuorideQZ glof mercury anda trace of hydrogen fluoride, is charged into a stainless "steel, autocrave and shaken 30 minutes at room temperaturefl libirrs:at 1 00 C., 2fhours"at 120 (3., and'6 hours at 140 C. After cooling and venting the vessel, the mixture j lved ,in benzene, separated" from mercury, filtered throughdiatomaceous earth. Evaporation of henz ene from the filtrate. under redu ced pressure leaves the product as a brown solidjSublirnation at 85 -95" C. a d 011 yields white crystals, 54-55 03.4 sam le for an'alysis is 'resublirned. j

of dry quinoline, and 3. ml.. of dry dimethylforrnarnide arestirred and heated to refluxingfor about 30' hours. After cooling and dilution with ether, the precipitate is removed by filtration and washed with ether. Solvents are evaporated from the filtrate under reduced pressure leaving the product as an oily.brown solid..- Purification is effected by column chromatography on 150 g. of silica, the product being eluted with benzene-hexane (3:1). The fractions whichshow one spot of Rf, 0.7 on a silica thin layer plate developed with benzene are combined. Evaporation ofthe solvents under reduced pressureleaves white crystals, M.P. 84-86 C. A sample fora'nalysis is sub-" liriied'fat 55 C. and 0.05 mm.; M.P.'8586.'C. {f "'j hlysis.-Calcd." fo'rC H F.N; C, 64.52; H, 3125; N,5.02.Fo'und: C, 65.50; H,3.04; N,4.52.

' 14 EXAMPLE 5 Lithium aluminum hydride; 250 mg. (0.0066 mole), is weighed under nitrogen, transferred to a dry, nitrogenflushed reaction flask, and suspended in 15 ml. of absolute ether. 'Asolution of 880 rrig. (0.0066 mole) of aluminum chloride in 15 ml.ot absolute ether is added dropwise. The mixture, containing a white precipitate, is stirredat room temperaturefor 5 minutes; then asolutior'i of 0'.942 g. (0.00338 mole) of 2-(a,a,)8,B-tetrafluorophenethyD-berizonitrile in 30ml. of absolute ether is added dropwise. The mixture is stirred at room temperature and in a nitrogen atmosphere forabout 18 hours. Hydrolysisiseffected by the dropwise addition of 4 ml. of water. After decantation of the ethereal layer and washing of the gelatinous precipitate with two portions of boilingether, theprecipitate is suspended in 20 ml. of 40% aqueous sodium hydroxide and 200 m1. of wafer. The mixture is extracted repeatedly with benzene-ether (1:1); Evaporation of solvents under reduced pressure from "the washed and dried organic extractleaves the product as the residual solid, M.P. 54-56 C. A sample is purified for analysis by sublimation at 47 C. and 0.05 mm.; '55-57 C.

Analysis.'Calcd. for C H F 'N: C, 63.57; H, 4.62; N, 4.94. Found: C, 63.93; H, 4.54; N, 4.94.

The basemay be converted to the hydrochloride salt by treating a solution in ethanol with a slight excess of ethanolic hydrogen chloride. Dilution with ether precipitates the hydrochloride, M.P. 244-247 C. Repeated recrystallizations from ethanol-ether and from isopropyl alcohol gives purified material, M.P. 253-254" C.

Analysis.-Calcd. for C H F,N-HCI: C, 56.35; H, 4.41; N, 4.38. Found: C, 56.53; H, 4.15; N, 4.45.

The lactate salt is prepared by treating a solution of 2-(ot,oz,,8,[3 tetrafluorophenethyl)benzylamine in ethanol with a; slight excess of -90% lactic acid. Dilution with ether precipitates the lactate, M.P. 144-146 C. The melting point is unchanged by recrystallization from isopropyl alcohol-ether.

Analysin-Cald. for C15H13F4N'C3HQO3: C, H, 5.13.1 Found: C, 58.06; H, 4.88. 7

. I V EXAMPLE 6 N;Methyl-2i- (a,c ,p,p-tetrafluorophenethyl)benzylamine 2 (ot,a,}9,fi tetrafiuo'r ophenethyl)benzylamine, 1.4 g. (0.0005 mole) in ml. of ethyl formate, is stirred and heated torefluxing for about 20 hours. Evaporation of the solution to dryness and trituration of the residual solid with-petroleum ether gives N-[2-(a',ct,p,B-tetrafluorophene ethyDbenZyIIfOrmamide, M.P. 61-75 C. 7

Lithium aluminum hydride, 290 mg. (0.0077 mole), is weighed under nitrogen, transferred to a dry, nitrogen flushedreaction flask, and suspended in 10 ml. of abso lute ether. A solution of 1.2 g. (0.00386 mole) of N-[Zf (a,a,fl,fl-tetratluorophenethyl)benzyl] formamide in 25 m1; of absolute ether is added dropwise and the mixture is stirred at reflux for about 18 hours. After the addition of absolute ether, the mixture is cooled in an ice-bath and hydrolysis is effected by the successive dropwise addition of v0.31r'nl f0f water, 0.2 ml. of 20% aqueous sodium hy-' droxide, and 0.6 ml. of water. The granular precipitate is filteredand washed with ether. Evaporation of the ethe; real filtrate under reduced pressure leaves the oily base as the residue. The base is converted to the hydrochloride salt by treating an ethanolic solution with a slight excess of ethanolic hydrogen chloride. The hydrochloride precipitates and after; recrystallization fromabsolute ethanol, is obtained as; white crystals, M.P. 251-253 C. A sample for analysis melts at 252-253" C. after recrystallization from absolute ethanol and from methanol-ether.

Analysis- -Calcd. for C H NHCl: C, 57.58; H, 4.83; N, 4.20. Found: C, 57.86; H, 4.68; N, 4.41.

EXAMPLE 7 N,N-dimethyl-2-(a,u,p,)8 tetrafiuorophenethyl)benzylamine j A' solution of, 2.2 g. (0.006 mole) of 2-(a,u,;S,,6-tetrafluorophenethyl)benzylamine (i) lactate in 3 ml..of 88% formic acid is treated with 1 g; (0.013 mole) of 37% formaldehyde and the stirred mixture is heated on the steam bath for about 18 hours. vAfter the addition of 1 ml. of concentrated hydrochloric acid, the so1ution is evaporated to dryness under reduced pressure. The res dual syrup is dissolved in ml. of Water and the solution is rendered strongly alkaline With 40% aqueous sodium hydroxide. The base is extracted into benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the product as the residual oil. The base is converted to the hydrochloride salt by treating a solution in isopropyl alcohol with a slight excessof 8.2 N hydrogen chloride in ethanol. The hydrochloride precipitates in white crystals, M.P. 190-192 C. The melting point is unchanged by recrystallization from isopropyl alcohol. I

Analysis.,Calcd. for C H F N-HCl: C, 58.71; H, 5.22; N, 4.03; Cl, 10.19. Found: C, 59.12; H, 5.22'; ,N, 3.83; CI, 10.10.

EXAMPLES 8-66 N,N-dialkyl-2- [2-(phenyl-1,1,2,2-tetrafiuoro)ethyl] benzylamine Using the appropriate starting materials, the following products are also prepared as set forth in the preceding description.

' Flow sheet Example mula A 'n X X PhenyL. 2 H Chloro. d0..-. 2 H.-. Fluoro. do 2 H. Methyl. do. 2 H. tert.-Butyl ...do.--. 2 H. Methoxy. -do..-. 2 H. Ethoxy. -do 2 H. Trifiuoromethyl --.do. 2 H. Methylsulionyl. -do 2 H... Methylmercapto. ..-do---. 2 H Dlmethylsultamoyl. 0-... 2 Methyl. .-.do.--- 2 D0. I o 2 Dimethylsulfamoyl. 0.... 2 Chloro. -do 2 H Do. 0-.-. 2 H Fluoro. .--do.-.. 2 H Methyl. 0.... 2 H. tert.-Bi1ty1 ---do-.-. 2 H. .0 Methoxy. .-.do.... 2 H u. Ethoxy. ...do.... 2 H..-. Trifluoromethyl. .-.do---. 2 H.... Methylsulfonyl. .-.do 2 H. Methylmercapto. .do 2 Dlmethylsultamoyl. -..d0- 2 Methyl. .do 2 0. o 2 Dimethylsulfamoyl. -do 2 Chloro. ..-do-.-. 2 H-.. o. 2 Fluoro. 2 Methyl. 2 tert.-Butyl 2 Methoxy.

2 Ethoxy. 2 Trifluoromethyl. 2 Methylsulfonyl. 2 Methylmercapto. 2 Dimethylsultamoyl. 2 Methyl. 2 Do. 2 Dlmethylsulfamoyl 2 hloro. 2 Do. 2 Fluoro. 2 Methyl. d 2 tert.-Butyl. d 2 Methoxy. d 2 Ethoxy. d 2 Tritluoromethyl. -do.... 2 H Methylsultonyl. -d0...-. 2 H. Methylmercapto. ...do..-.. 2 Dimethylsultamoyl. -.-do 2 Methyl.-. ethyl. ...do..... 2 Chloro--. Do. ---do...-. 2 .--.-do Dlmethylsulfamoyl.

V TABLE Contlnued F-lovv i I sheet l- Example mula I X 2-....do Chloro. 2 Derivatlvesol each of the compounds of Formula IV above-in which R: and R; are methyl, ethyl,

. propyhbutyl or amyl.

2 Der.vatlves 01 compounds of Formula IV above in. which. Alk' is methyl, ethyl, propyl, butylpor amyl. H 2 Derivatives of the compounds of Formula IV above in which is l-piperldyl, l-pyrrolldinylj 4-thlomorpho1lnyl or l-lower 'alkyl--piperazinyl, and in which 66 H E/ --gdo...

When the procedures of Examples 8-66 are repeated using appropriate amounts'of the corresponding starting materials except that the A-substituent is either pyridine, pyrimidine, thiazole, thiophene, imidazole or oxazole, the corresponding products are obtained.

In a dry'apparatus maintained under a nitrogen atmosphere, 40 mg. (0.00165 g. atom) of magnesium turnings are suspended in 0.5 ml. of tetrahydrofuran containing a crystal of iodine. A solution of 0.5 g. (0.0015 mole) of 2-bromo-a,a}:',a-tetrafiuorobibenzyl in. 1.5. ml. of tetrahydrofuran and a solution of 0.3 g. of ethylene bromide in 4 drops of 'fetrahydrofuran are added dropwise alternately until the're'action is initiated. The mixture thenis heated to refluxing and the remaining solution of the 2-bromo-u ,o ,a',a'-tetrafluorobibenzyl is added. Refluxing is continued until all of the magnesium. is con? sumed. The mixtureis cooled in ice and diluted .with 3 ml. of tetrahydrofuran. Carbondioxide is passed over thesurface of the stirred mixture for 1 hour and then passed through the solution for 3 minutes. After another 1 hour inthe cold, the mixture is allowed tostand at room temperature for about 1 6v hours. i

The bulk of the solvent is evaporated under reduced pressure-and below 40 C. and the residue is dissolved in benzene. After treatment of the ice-cold solutionwith water and dilute hydrochloric acid, the organic phase is separated, washed with water, and evaporated'to dry; ness under reduced pressure. The residual oil is 't'riturated with 1 N sodium hydroxide and the mixture is centrifuged. The clear supernatant alkaline solution is decanted, acidified with '6 N hydrochloric acid, and the solid product extracted into benzene. Evaporation of the washed benzene extract and recrystallization of the residual solid from hexane gives white crystals, M.P. 130- 132 C. An analytical sample melts'at 131-132 C. after r'ecrystal lization from cyclohexane and sublimation at and 0.2 mm. I i

Analysis.--Calcd. for CHI-F402: C, H, 3.38; Found: C, 60.45; H, 3.48. a

EXAMPLE 69 2 (u,a, 3,18, -hexafluorophenylpropyl)benzylamine (A) Into'a round bottom flask equipped with a paddle stirrer is placed 19.3 g. (0.482 mole) of sodium hy-. droxide, 134.5 g. of water, 68.8 g. of 95% ethanol,,and 45.4 g. (0.38 mole) of acetophenone. The solution is stirred vigorously and is cooled in an ice bath such that 17 the temperature is kept between 15 C. and 30 C. 2-bromobenzaldehyde (69.89 g., 0.378 mole) is added all at once and the mixture is stirred vigorously for several hours. After standing at room temperature overnight, the mixture is diluted with 300 ml. of ether. The ether phase is separated and is washed with water until the washings are neutral to litmus paper. The ether solution is dried (MgSO and removal of the ether gives 103.8 g. of 2-bromobenzalacetophenone as a yellow oil.

'(B) 2-bromobenzalacetophenone (103.8 g., 0.37 mole) is dissolved in 226 ml. of carbon tetrachloride. The solution is stirred and cooled in an ice bath. Bromine (60.50 g., 0.38 mole) is added dropwise over a period of 0.5 hour, and after this addition is complete, the mixture is stirred another 0.5 hour. The crystalline product is removed by filtration, and is washed with hot absolute ethanol, and dried to give 87.7 g. of Z-bromobenzalacetophenone dibromide.

(C) 2-bromobenzalacetophenone dibromide (87.7 g., 0.196 mole) is placed in a round bottom flask equipped with stirrer, dropping funnel, and reflux condenser with calcium chloride drying tube. Dry methanol (100 ml.) is added and the mixture is stirred. A solution of 9.01 g. (0.392 mole) of sodium in 95 ml. of absolute methanol is added rapidly and the mixture is heated under reflux for one hour. The cooled mixture is made neutral by addition of approximately 0.5 ml. concentrated hydrochloric acid and is diluted with 65 ml. of water. On stirring the mixture, crystallization occurs. The product is removed by filtration, washed with Water, absolute methanol, and finally is recrystallized from methanol to give 35.90 g. of 3-(2-bromophenyl)-3-methoxy-1-phenylpropen-l-one.

(D) A mixture of 19.34 g. of 3-(2-bromophenyl)-3 methoxy 1 phenylpropen 1 one, 200 ml. of absolute methanol and 20 ml. of 6 N hydrochloric acid is stirred and refluxed for 1.5 hours. The bulk of methanol is evaporated off on a rotary evaporator at 60 C. The residue is diluted with water (500 ml.) and is extracted with two 200 ml. portions of benzene. These benzene extracts are combined, washed with water, saturated sodium bicarbonate solution, water, and dried over magnesium sulfate. Filtration and evaporation of the benzene gives 19.19 g. of (2-bromobenzoy1)-benzoylmethane.

(E) Into a round bottom flask equipped with a dropping funnel, thermometer, stirrer, gas inlet tube and gas outlet tube is placed 15.35 g. (0.0615 mole) of (2-bromobenzoyl)-benzoylmethane and 5 ml. of chloroform. The solution is cooled in an ice bath from C. to 15 C. and a solution of bromine (21.7 g., 0.135 mole) in 55 ml. of chloroform is added dropwise over 30 minutes. During this addition, a stream of air is passed over the surface of the solution to blow out the by-product of hydrogen bromide. After the addition is completed, the solution is stirred for an additional 15 minutes, and then the chloroform is removed on a rotary evaporator at a temperature of 25 C. to 40 C.

To the oily residue is added a hot solution of 11.2 g. (0.136 mole) of freshly fused sodium acetate dissolved in 55 ml. of glacial acetic acid. The solution is stirred magnetically and is heated under reflux for 2 hours. The bulk of the acetic acid is removed by evaporation on the rotary evaporator. The residue is dissolved in ether and this ether phase is washed with water (X 250 ml.) and dried over magnesium sulfate. Evaporation of the ether gives a bright orange, viscous syrup that is distilled at 170-195 C. (0.5 mm). This distillate is redistilled to give 1-(2-bromophenyl) 3-phenylpropan 1,2,3 trione, B.P. 174177 C. (0.3 mm.), 8.31 gm.

Analysis.-Calcd. for C 5HgBIO I C, 56.81; H, 2.86. Found: C, 56.63; H, 3.02.

(F) A mixture of 8.31 g. (0.0262 mole) of 1-(2bromophenyl) 3 phenylpropan-1,2,3-trione, 112 g. of sulfur tetrafluoride, 1 g. of mercury and ml. of hydrogen fluoride is heated in a stainless steel bomb at 100 C. for two 18 hours, C. for two hours, and C. for 6 hours. The cooled contents of the bomb are dissolved in hexane and filtered. Evaporation of the hexane from the filtrate gives a light tan oil. Fractional distillation of the oil gives 2-(a,a,/3,fi,'y,'y hexafluorophenylpropyl) bromobenzene, B.P. 83-87 C. (0.05 mm.), 4.64 g.

Analysis.Calcd. for C H BrF C, 47.02; H, 2.37; F, 29.75. Found: C, 46.94; H, 2.67; F, 29.52.

(G) A mixture of 4.64 g. (0.0121 mole) of 2-(a,a,fi,fi, hexafluorophenylpropyl) bromobenzene, 1.19 g. (0.0133 mole) of cuprous cyanide, 46 ml. of quinoline, and 4.6 ml. of dimethylformamide is stirred magnetically and heated under reflux for 24 hours. The dark reaction mixture is diluted with ether and 6 N hydrochloric acid, and the entire mixture is filtered through a pad of diatomaceous earth. The ether phase is withdrawn and is washed with 3 N hydrochloric acid, water, and dried over magnesium sulfate. Evaporation of the ether gives 4.06 g. of oil that distills at 137-140 C. (1.0 mm). This distillate crystallizes immediately and is recrystallized from hexane to give 2.37 g. of sparkling white plates, MP. 72- 73 C.

(H) To a solution of 0.46 g. (0.012 mole) of lithium aluminum hydride in 20 ml. of dry ether is added dropwise over 15 minutes a solution of 1.6 g. (0.012 mole) of aluminum chloride dissolved in 25 ml. of ether. The solution is stirred for approximately 15 minutes, then a solution of 2.00 g. (0.00608 mole) of 2-(oc,a, 3,fi,'y,'y-heXafll10- rophenylpropyl)benzonitrile dissolved in 25 ml. of dry ether is added dropwise over 15 to 20 minutes. The mixture is stirred overnight at room temperature.

The excess lithium aluminum hydride is decomposed by dropwise addition of 5 N sodium hydroxide until a clear ether phase is obtained. The ether is decanted and the gelatinous residue that remains is thoroughly extracted with ether (3 X 100 ml.). The ether phases are combined and dried (*MgSOg). Evaporation of the ether gives 1.98 g. of a clear, colorless oil. This oil is dissolved in ether and is treated with dry, gaseous hydrogen chloride. The white, crystalline precipitate is removed by filtration and is recrystallized from ethyl acetate to give 2-(ot,oz, 3,[3,'y,'yhexafluorophenylpropyl)benzylamine hydrochloride, M.P. 162163.5 C.

Analysis.--Calcd. for C H F N-HCl: 'C, 52.12; H, 3.55; Cl, 9.61; F, 30.92. Found: C, 52.42; H, 3.77; Cl, 9.53; F, 30.70.

(EXAMPLE 70 4-fluoro-2- (c n, 13,;3-tetrafluorophenethyl) benzylamine (A) 2-bromo-4-fluorobenzonitrile.--A solution of 10.9 g. (0.05 mole) of 2-brorno-4-fluorobenzamide in 50 ml. of dry pyridine is stirred and cooled in an ice-bath While 11.2 g. (0.0525 mole) of trifluoroacetic anhydride is added dropwise. After 2 hours at room temperature, the bulk of the solvent is evaporated under reduced pressure and the residue is dissolved in ether. Evaporation of the washed and dried ethereal extract under reduced pressure leaves the product as the residual solid. Sublimation at 55 a C. and 0.05 mm. yields white crystals, M.P. 75-

76.5 C. A sample from a previous experiment was resublirned for analysis, M.P. 77-78 C.

Analysis.-Calcd. for C I-I -BrFN: C, 42.00 H, 1.50; N, 7.00. Found: C, 41.41; H, 1.68; N, 6.92.

(-B) 2'-bromo-4-fluoro 2 phenylacetophenone.-A solution of 2-bromo 4 fluorobenzonitrile, 6.0 g. (0.03 mole) in 35 ml. of absolute ether is added dropwise to a stirred solution of benzylmagnesium chloride prepared from 2.9 g. (0.12 g. atom) of magnesium turnings and 15.2 g. (0.12 mole) of benzyl chloride in 65 ml. of abso lute ether in a nitrogen atmosphere. The mixture is stirred at room temperature for about 18 hours. After cooling in an ice-bath, the adduct is hydrolyzed by the dropwise addition of 100 ml. of 0.5 M citric acid. The organic phase is separated and the aqueous phase reextracted with several portions of benzene. The combined organic layers are extracted with 45 m1. of ice-cold 6 N hydrochloric acid in several portions and the combined acid extracts are heated on the steam bath for 45 minutes. The product separates as an oil and is extracted into benzene. Evaporation of the washed and dried benzene extract leaves the yellow oily product that is purified by distillation; B.P. 11211'5 C./0.05 mm.

(C) Z-bromo-4-fluorobenzil.By following essentially the same procedures described in Example 2, 2'-bromo-4'-fluoro-2-phenylacetophenone is oxidized to 2-bromo-4-fluorobenzil. The yellow crystalline product, M.P.

62-66 C., is recrystallized from 95% ethanol to obtain material of M.P. 67-68.5 C. A sample for analysis melts at 67.5-69? C. after sublimation at 60 and 0.1 mm.

Analysis.-Calcd. for C H BrFO C, 54.72; H, 2.61; Br, 26.06. Found: C, 55.08; H, 2.84; Br, 25.75.

(D) 2-bromo-4,u,6,6,a'-pentafluorobibenzyl.-By following essentially the same procedures described in Example 3, 2-bromo-4-fiuorobenzil is converted to 2- bromo-4,a,a,a,a'-pentafluorobibenzyl. Sublimation of the crude brown solid at 50 C. and 0.1 mm. yields white crystals, M.P. 47-48" C. A sample for analysis is resublimed.

Analysis.-Calcd. for C H BrF C, 47.89; H, 2.30; Br, 22.76. Found: C, 48.44, H, 2.53; Br, 22.47.

(E) 4-fll101'O-2-(a,0t,,3,fi tetra fluorophenethyl)benzonitrile.A mixture of 4.9 g. (0.0139 mole) of 2-bromo- 4,01,66,6t,a'-pentafluorobibenzyl, 3.70 g. of cuprous cyanide, '60 ml. of dry quinoline and 6 ml. of dry dimethylformamide is stirred and heated to refluxing for 18 hours. After cooling in ice, the precipitate is removed by filtration and washed with a mixture of benzene and ether. Solvents are evaporated from the filtrate under reduced pressure leaving the crude product as an oily black solid. Purification is effected by column chromatography on 300 g. of silica, the product being eluted with benzene-carbon tetrachloride (2:1). The fractions containing a major component of R) 0.65 on a fluorescent silica thin layer plate developed with benzene are combined. Evaporation of the solvents under reduced pressure leaves a solid that is sublimed at 60 C. and 0.1 m-m.; M.P. 68-70 C. A sample for analysis is resublimed. Analysis.Calcd. for C H F N: C, 60.62; H, 2.71;

' N, 4.71. Found: c, 61.33; H, 2.76; N, 4.70.

'amine.By following essentially the same procedures described in Example 5, 4-fluoro-2-(a,u,B,fi-tetrafluorophenethyl)benzonitrile is reduced to 4-fiuoro-2-(a,a,[3,,B- tetrafluorophenethyl)benzylamine. Sublimation of the crude product at 70 C. and 0.05 mm. gives white crystals, M.P. 52.5-54 C. A sample for analysis is resublimed; M.P. 53-54.5 C.

Analysis.-Calcd. for C H F N: C, 59.80; H, 4.02;

" N, 4.65. Found: c, 60.11; H, 4.07; N, 4.61.

EXAMPLE 71 2-(4,a,u,flfi-pentafluorophenethyl)benzylamine Br, 27.27. Found: C, 53.04; H, 3.59; Br, 26.83.

(B) 2-bromo-4'-fiuorobenzil.By following essentially the same procedures described in Example 2, 2'-bromo- 2-(p-fluorophenyl)-acetophenone is oxidized to 2-bromo- 4'fluorobenzil. The yellow crystalline product, M.P. 72-- ;78 C., is recrystallized from 95% ethanol to obtain.

material of M.P. 76.5-78.5 C. Repeated recrystallization from'95% ethanol yields a sample for analysis, M.P. 79-

Analysis.-Calcd. for C H BrFO C, 54.72; H, 2.61; Br, 26.06. Found: C, 55.07; H, 2.67; Br, 25.93.

(C) 2-bromo-4',a,a,a.',a'-pentafiuorobibenzyl. By following essentially the same procedures described in Example 3, 2-bromo-4-fiuorobenzil is converted to 2- bromo-4,a,o e,dpentafluorobibenzyl. Sublimation of the crude brown solid at 6070 C. and 0.1 mm. yields white crystals, M.P. 52-53.5 C.

Analysis.-Calcd. for C14H8B1'F5I C, 47.89; H, 2.30; Br, 22.76. Found: C, 48.21; H, 2.37; Br, 23.04.

(D) 2-(4,a,6t,;8,,B-pentafluorophenethyl)benzonitrile.- A mixture of 8.5 g. (0.024 mole) of 2bIOIn0-4,u,0c,a',m'- pentafluorobibenzyl, 6.4 g. of cuprous cyanide, ml. of dry quinoline and 7.5 ml. of dry dimethylformamide is stirred and heated to refluxing for 34 hours. The precipitate is removed from the cooled mixture by filtration and washed with a mixture of benzene and ether. Solvents are evaporated from the filtrate under reduced pressure leaving the product as an oily black solid. Sublimation at C. and 0.05 mm. yields light brown solid, M.P. 93 C. Purification is effected by column chromatography on 300 g. of silica, the product being eluted with benzene-hexane (1:1). The fractions that show one spot of R 0.85 on a fluorescent silica thin layer plate developed with benzene are combined. Evaporation of the solvent under reduced pressures leaves white crystals, M.P. 96.5-97.5 C. A sample for analysis is sublimed.

Analysis.Calcd. for C H F N: C, 60.62; H, 2.71; N, 4.71. Found C, 60.81; H, 2.57; N, 4.57.

(E) 2 (4,ot,u,fl,f3 pentafluorophenethyl)benzylamine.--By following essentially the same procedures described in Example 5, 2-(4,a,a,B,fi-pentafluorophenethyl)- benzonitrile is reduced to 2-(4,oc,a,,8,B pentafiuorophenethyDbenZylamine. The crude product, M.P. 64-66 C., is sublimed at 60 C. and 0.05 mm. yielding white crystals, M.P. 6465.5 C.

Analysis.-Calcd. for C H F N: C, 59.80; H, 4.02; N, 4.65. Found: C, 59.80; H, 3.93; N, 4.67.

EXAMPLE 72 2-[2-(a,a,5,,8-tetrafiuorophenethyl)phenyl]- imidazoline 2 (a,a,,8,;8 tetrafluorophenethyl)benzonitrile, 2.06 g. (0.0074 mole), together with 1.2 g. (0.02 mole) of ethylenediamine and 3 drops of carbon disulfide, is heated in a sealed tube at -165 C. for 18 hours. After cooling in an ice-bath, the tube is opened and the contents are poured into water. The orange gum that separates is washed with water by decantation and then dissolved in ethyl acetate. The ethyl acetate solution is extracted with 3 N hydrochloric acid. The combined, ice-cold, acid extracts are rendered strongly alkaline With 40% aqueous sodium hydroxide and the oily base is extracted into ethyl acetate. The washed and dried ethyl acetate extract is concentrated under reduced pressure to a volume of about 25 ml. and 0.6 ml. of 8 N ethanolic hydrogen chloride is added. Dilution with an equal volume of absolute ether precipitates the white crystalline hydrochloride salt of the product, M.P. 263266 C., sintering at 258 C. Recrystallization from acetone gives a purified sample, M.P. 266267 C.

Analysis.-Calcd. for C H F N 'HCl: C, H, 4.21; N, 7.81. Found: C, 56.94; H, 4.03; N, 7.60.

EXAMPLE 73 2- (u,a,/3,B-tetrafluorophenethyl) phenethylamine (A) 2 (0L,I.!,)3,B tetrafiuorophenethyl)benzyl alcohol.Lithium aluminum hydride, 530 mg. (0.0139 mole), is Weighed under nitrogen, transferred to a dry-nitrogenfiushed reaction flask, and suspended in 15 ml. of absolute ether. A solution of 4.15 g. (0.0139 mole) of 2 (a,ot,fl,fltetrafluorophenethyl)benzoic acid in 35 ml. of absolute ether is added dropwise. The mixture is stirred at room temperature for 30 minutes and allowed to stand overnight in a nitrogen atmosphere. Hydrolysis is effected by the dropwise addition of 1 ml. of water. The precipitate is removed by filtration, and washed with ether. Evaporation of the dried ethereal filtrate under reduced pressure leaves the product as a White solid, M.P. 80-81 C. A sample for analysis is sublimed at 70 C. and 0.1 mm.

Analysis.Calcd. for C H F O: C, 63.37; H, 4.26; F, 26.74. Found: C, 63.78; H, 4.27; F, 26.38.

(B) 2-(a, 8,fi-tetrafiuorophenethyl)benzyl bromide.- A suspension of 3.3 g. (0.0116 mole) of 2 (a,a,/3,,8- tetrafluorophenethyl)benzyl alcohol in 15 ml. of 48% hydrobrornic acid is stirred and heated on the steam bath for 3 hours. The product crystallizes from the cooled mixture and is collected and dissolved in benzene. Evapora: tion of the washed and dried benzene extract under reduced pressure and sublimation of the residual solid at 60 C. and 0.05 mm. yields white crystals, M.P. 70-77 C. A sample for analysis from a previous preparation was purified by column chromatography on silica, eluting the product with benzene-carbon tetrachloride (2:1). The fractions that showed one spot of Rf 0.85 on a fluorescent silica, thin layer plate developed with benzene were combined and the solvent evaporated under reduced pressure. The residual solid, M.P. 78-82 C., was sublimed at 60 C. and 0.05 mm. to yield product, M.P. 80.582" C.

Analysis.-Calcd. for C H BrF C, 51.89; H, 3.20; Br, 23.02. Found: C, 52.18; H, 3.32; Br, 22.89.

(C) 2- (ogufifi tetrafluorophenethyl)phenylacetonitrile.--2 (a,a,5,;8 tetrafluorophenethyl)benzyl bromide, 3.5 g. (0.01 mole), and 2.0 g. (0.0308 mole) of potassium cyanide are dissolved in 35 ml. of acetone-5 ml. of water and the solution is heated to refluxing for about 18 hours. The organic phase is separated, acetone is distilled under reduced pressure, and the residual oil is dissolved in benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the product as the residual brown oil.

(D) 2 (oc,a,B,{3 tetrafluorophenethyl)phenethylamine.By following essentiall the same procedures described in Example 5, 2 (a,a,B,fl-tetrafluorophenethyl) phenylacetonitrile is reduced to 2 (a,a,/3,,B tetrafluorophenethyl)phenethylamine. The product, a yellow oil, is converted to the hydrochloride salt by treating an ethanolic solution with a slight excess of 8.2 N hydrogen chloride in ethanol. Dilution with absolute ether pre cipitates the product as white crystals, M.P. 212-214 C. Recrystallization from absolute ethanol-absolute ether yields a purified sample, M.P. 2135-2155 C.

Analysis.-Calcd. for C H F N-HCl: C, 57.58; H, 4.83; N, 4.20. Found: C, 57.88; H, 4.78; N, 4.25.

A mixture of 3.9 g. (0.0138 mole) of 2-(u,a,)3,B-tetra fluorophenethyl)benzylamine, 1.77 g. (0.014 mole) of benzyl chloride, 2.5 g. of anhydrous potassium carbonate, and 25 ml. of benzene is stirred and heated to refluxing for about 40 hours. After filtration, the solvent is evaporated under reduced pressure, leaving the product as the residual oil. Purification is effected by column chromatography on 250 g. of silica, the product being eluted with 1%methanol in chloroform. The fractions that show one spot of Rf 0.7 on a fluorescent silica thin layer plate developed with 5% methanol in chloroform are combined. Evaporation of the solvent under reduced pressure leaves the product as the residual oil. The base is converted to the hydrochloride salt by treating an ethanolic solution with a slight excess of 8 N hydrogen chloride in ethanol. Dilution with absolute ether precipitates the hydrochloride .as white crystals, M.P. 188189.5 C. Recrystallization from acetone .yields a purified sample, M.P. 1885-190 C. v

, Analysis.Ca1cd. for C H F N-HCl: C, 64.48; H, 4.92; Cl, 8.65. Found: C, 64.75; H, 4.89; Cl, 8.64.

22 EXAMPLE 7s a-MethyI-Z- a, oz, ,8, fi-tetrafluoro phenethyl benzyl amine (A) Methyl Z-(a,ot,fi,fi tetrafluorophenethyl)phenyl ketimine.-A solution of 19.3 g. (0.0685 mole) of 2- (o e n,B-tetrafluorophenethyl)benzonitrile in 150 ml. of absolute ether is added dropwise to a stirred solution of methyl-magnesium bromide prepared from 4.8 g. (0.2 g. atom) of magnesium turnings and about 25 g. (0.26 mole) of methyl bromide in 150 ml. of absolute ether in a nitrogen atmosphere. The mixture is stirred at reflux for about 16 hours. After cooling in an ice-bath, the adduct is hydrolyzed by the dropwise addition of 20 ml. of water. The organic phase is decanted and the gelatinous precipitate is washed thoroughly with ether. The combined ethereal extracts are extracted with 45 ml. of ice-cold 6 N hydrochloric acid in several portions. After further chilling of the combined acid extracts, the precipitate of the hydrochloride salt of the product is collected and washed with ether. After prolonged drying in vacuo, the crystalline hydrochloride melts at 144-146 C., with previous sintering. Repeated recrystallizations from isopropyl alcohol-absolute ether afford an analytical sample, M.P. 147148.5 C.

Analysis.-Calcd. for C H F N-HCl: C, 57.94; H, 4.25; N, 4.22. Found: C, 58.08; H, 4.18; N, 4.39.

(B) a-Methyl-Z (a,a,fi,fi-tetrafluorophenethyl)benzylamine.Lithium aluminum hydride, 1.05 g. (0.0276 mole), is weighed under nitrogen, transferred to a dry, nitrogen-flushed reaction flask, and suspended in 25 ml. of dry, peroxide-free, tetrahydrof'uran. The mixture is stirred and cooled in an ice-bath while a solution of 4.3 g. (0.013 mole) of methyl 2-(a,a,{3,/8-tetrafluorophenethyl)phenyl ketimine hydrochloride in 70 ml. of tetrahydrofuran is added dropwise. The mixture is stirred at room temperature and in a nitrogen atmosphere for about 18 hours. After cooling in an ice-bath, hydrolysis is effected by the successive dropwise addition of 1 ml. of water, 1 ml. of 20%. aqueous sodium hydroxide, and 3 ml. of water. The precipitate is removed by filtration and washed with ether. Evaporation of the dried ethereal filtrate under reduced pressure leaves the product as the red oily residue.

The base may be converted to the hydrogen maleate salt byheating a solution in isopropyl alcohol with a slight excess of a solution of maleic acid in isopropyl alcohol. Dilutionwith absolute ether precipitates the hydrogen maleate as white crystals, M.P. 153-154 C. dec. Repeated recrystallizations from isopropyl alcohol-ether afford purified material, M.P. 157-158 C. dec.

Analysis.-Calcd. for C15H15F4N'C4H404: C, H, 4.63. Found: C, 58.11; H, 4.64.

EXAMPLE 76 Prevention or modification of ventricular arrhythmia Beagle dogs of either sex and weighing from 6 to 10 kg. are anaesthetized by the administration of vinbarbital employing a dose of 50 rug/kg. of body weight and the mean arterialpressure and the electrocardiogram (Lead II) are recorded. The animals are artificially respired and the thorax opened at the fourth or fifth interspace. The pericardium is opened and a portion of the anterior descending coronary artery just distal to the origin is freed fromthe surrounding tissue. Mecamylamine is adminis tered to slow the heart rate and l0 minutes later the compound to be tested for antia-rrhythmic effect is administered intravenously. Ten minutes after administration of the test compound, 0.0 035 mL/kg. of tetrafluorohexachloro'butane (TFHCB), a sclerosing agent which produces myocardial infarction and arrhythmia in dogs (Ascanio et al., I. Am. Physiol., 209:1081-1088 (1965)) is injected into the coronary artery. In control animals, this dose of TFHCB produces a ventricular arrhythmia in of the animals tested and death in 33% of the animals tested as a result of ventricular fibrillation.

Followinginjection of the sclerosing agent, an electrocardiogram is recorded at two-minute intervals for one hour and the average number of electrical (ECG) complexes per minute and the percent normal complexes calculated. The data obtained with difierent doses of the test compounds is plotted and the dose estimated to protect the animals is estimated graphically (ED mg./kg.). This figure indicates that 80% of all the electrical (ECG) complexes are normal.

The compound 2 (a,u,fi, 3-tetrafluorophenethyl)- benzylamine is tested at doses of from 0.02 to 2.5 mg./kg. The average per cent of normal complexes calculated is from 20 to 97. Thus, the estimated ED is equal to 0.16 mg./kg. compared with quinidine sulfate which, when tested under similar conditions at doses of 2.5, 5.0 and 10.0 mg./kg. gave average percent of normal values of 25, 51 and 90, respectively, giving an estimated ED =8.8 mg./kg.

EXAMPLE 77 Capsules Capsules for oral administration are prepared by dispersing the active ingredient in lactose and magnesium stearate and encapsulating the mixture in standard soft gelatin capsules so that each capsule will have the following composition.

Per capsule, mg. 2- (a, 01, 53, fl-tetrafluorophenethyl benzylamine hydrochloride 5 Lactose 430 Magnesium stearate 5 EXAMPLE 78 Parenteral solution A solution suitable for administration for injection is prepared by mixing the active ingredient, dextrose, methylparaben, propylparaben and distilled water, so that each one will have the following composition, and sterilized.

Tablets for oral administration are prepared by mixing the active ingredient with appropriate amounts of excipients and binding agents, formed into tablets by a conventional tableting machine, and coated so that each tablet will have the following composition.

Per tablet, mg. 2-(a,u,B,B-tetrafluorophenethyl)- benzylamine hydrochloride l0 Cellulose filter aid 11 Lactose 9 Calcium phosphate dibasic 143 Guar gum 6.1 Corn starch 4 Magnesium stearate 0.9 Opaque yellow film coating 3 The preceding three examples, Examples 77, 78 and 79, are repeated, and compositions for the treatment or prevention of arrhythmia are prepared by substituting any of the compounds specifically illustrated above in place of the tetrafluorophenethylbenzylamine as one of the active compounds useful in our invention.

EXAMPLE a,N-dimethyl-2- (1,11, fifi-tetrafluorophenethyl) benzylamine a Methyl 2 (0c,a,fl,]3 tetrafluorophenethyl) benzylamine, 1.06 g. (0.00357 mole), in 50 ml. of et hylformate is stirred and heated to refluxing for about 21 hours. Evaporation of the solution to dryness and trituration of the residue with hexane gives N-[a-methyl-2-(a,a, 8,;8- tetrafiuorophenethyl)-benzyl]-formamide, M.P. 94.5-99 C. Recrystallizations from ether-petroleum ether and isopropyl alcohol-water aiford a purified sample, M.P. 103- 105 C.

By following essentially the same procedures described in Example 6, N-[a-methyI-Z-(a,a, 8, 3-tetrafluorophenethyl)-benzyl-formamide is reduced to 0:,N-dil1'16lhYl-2- (a,a,[3,fl-tetrafiuorophenethyl)-benzylamine. The product, a yellow oil, is converted to the hydrogen fumarate salt by treating an ethereal solution with a solution of a slight excess of fumaric acid in absolute ethanol. The hydrogen fumarate precipitates and after recrystallization from acetone, is obtained as white crystals, M.P. 176 C. The melting point is unchanged by further recrystallization from acetone.

Analysis.-Calcd. fOl' C17H17F4N'C4H404: C, H, 4.95; N, 3.28. Found: C, 58.84; H, 5.09; N, 3.28.

The hydrochloride salt is prepared by treating a solution of the base in absolute ethanol with a slight excess of ethanolic hydrogen chloride. Dilution with absolute ether precipitates the hydrochloride that is recrystallized from acetone-absolute ether to obtain the analytical sample, M.P. -192 C.

Analysis.Calcd. for C17H17F4N'HCII C, 58.71; H, 5.22; N, 4.05. Found: C, 58.47; H, 5.40; N, 4.08.

EXAMPLE 81 o,N-dimethyl-2-(a,a,p,B-tetrafiuorophenethyl)- benzylamine Racemic a,N-dimethyl-2- (a,a,13,,8-tetrafluorophenethyl) benzylamine, 9.5 g. (0.0305 mole), in 25 ml. of boiling absolute ethanol is treated with a solution of 2.3 g. (0.0153 mole) of tartaric acid in 20 ml. of absolute ethanol. Crystallization is initiated by seeding and the solution is allowed to stand at room temperature until no further precipitation occurs. After collection of the tartrate, the ethanolic mother liquor is evaporated to dryness under reduced pressure and the residual solid suspended in water. The mixture is rendered alkaline with saturated sodium carbonate solution and the oily base is extracted into hexane. Evaporation of the Washed and dried hexane extract under reduced pressure leaves the base weighing 1.35 g.

The base is dissolved in 4 ml. of absolute ethanol and treated with a solution of 326 mg. (0.00217 mole) of tartaric acid in 3 ml. of absolute ethanol. The tartrate separates in white crystals, M.P. 183l86 C., yield, 1.3 g. Five recrystallizations from absolute ethanol give product of constant specific rotation; [a] =+18.75.

The tartrate is suspended in water and the mixture made basic with saturated sodium carbonate solution. The oily base is extracted into hexane. Evaporation of the washed and dried hexane extract leaves the base as the residual pale yellow oil; [a] =+31.76.

EXAMPLE 82 a,N dimethyl 2 (a,oc,fi, 3 tetrafluorophenethyl)- benzylamine (-)-tartrate obtained by the procedure described in Example 81, 9.6 g. (0.0249 mole) is suspended in water and the mixture made basic with saturated sodium carbonate solution. The oily base is extracted into hexane. Evaporation of the washed and dried hexane extract leaves the base as the residual pale yellow oil. The base, 7.65 g. (0.0246 mole), is dissolved in 20 ml. of absolute ethanol and treated with a solution of 1.85 g. (0.0123 mole) of tartaric acid in 20 ml. of absolute ethanol. Crystallization is initiated by seeding and the solution is allowed to stand at room temperature until no further precipitation occurs. After collection of the tartrate, the ethanolic mother liquor is evaporated to dryness under reduced pressure and the residual solid suspended in water. The mixture is rendered alkaline with saturated sodium carbonate solution and the oily base is extracted into hexane. Evaporation of the washed and dried hexane extract under reduced pressure leaves the base weighing 1.09 g.

The base is dissolved in 4 ml. of absolute ethanol and treated with a solution of 262 mg. (0.00175 mole) of tartaric acid in 2 ml. of absolute ethanol. The tartrate separates in white crystals, M.P. 184-187 C.; yield, 1.1 g. Three recrystallizations from absolute ethanol give product of constant specific rotation; [a] =-21.82; M.P. 190-192 C.

AMZYSZkr-CfilCd. fOI' C17H17F4NJ/2C4H406: C, H, 5.22; N, 3.62. Found: C, 59.25; H, 5.30; N, 3.49.

The tartrate is suspended in water and the mixture made basic with saturated sodium carbonate solution. The oily base is extracted into hexane. Evaporation of the washed and dried hexane extract leaves the base as the residual pale yellow oil; [u] '=--32.17.

(A) 2,2 dimethyl ot,lx,0t',ot' tetrafluorobibenzyl.-- o-Tolil, 4.76 g. (0.02 mole), together with 41 g. of sulfur tetrafluoride, 1.3 g. of mercury, about 1 g. of hydrogen fluoride and 40 ml. of benzene, is charged into a stainless steel autoclave and heated for 10 hours at 80 C. After cooling and venting the vessel, the mixture is separated from mercury and filtered. Evaporation of benzene from the filtrate under reduced pressure leaves a brown residue that is triturated with hot cyclohexane and filtered. Evaporation of cyclohexane from the filtrate under reduced pressure leaves the product as a brown solid. Sublimation at 105 C. and 0.05 mm. yields White crystals, M.P. 71.5- 73.5 C. A sample for analysis melts at 73-75 C. after recrystallization from hexane.

Analysis.-Calcd. for C H F C, 68.08; H, 5.00. Found: C, 67.76; H, 5.00.

(B) t,0t,0L',0t'-T6tlflflll0f0ethylene-2,2'-blS (benzyl bromide).-A mixture of 1.41 g. (0.005 mole) or 2,2-dimethyl-0L,I1,0t',0(.'-ttfflflllOI'OblbBIlZyl, 1.78 g. (0.01 mole) of N-bromosuccinimide, a trace of benzoyl peroxide, and 60 ml. of carbon tetrachloride is stirred at reflux for 7 hours. After cooling, the precipitate, a mixture of product and succinimide, is collected, dried and triturated with aqueous sodium hydroxide. The insoluble product is collected, washed with water, dried, and recrystallized from benzene to give white crystals, M.P. 178-183 C. Repeated recrystallization from benzene affords the analytical sample, M.P. 184-186 C.

Analysis.-Calcd. for C H Br F C, 43.67; H, 2.75. Found: C, 43.94; H, 2.77.

(C) a,ct,ot',a-Tetrafiuoroethylene 2,2 bis (benzylhexaminium bromide).Hexamine, 6.44 g. (0.046 mole), is dissolved in 75 ml. of boiling chloroform; 10.1 g. (0.023 mole) of a,a,at,ot'-tetrafluoroethylene-Z,2'-bis (benzyl bromide) is added and the mixture is heated to refluxing for 8 hours. After cooling, the precipitate is collected, washed with absolute ether, and dried to yield white crystalline solid, M.P. 186190 C. dec.

(D) c n,a',a-Tetrafluoroethylene 2,2 bis (benzylamine).--A mixture of 17.2 g. (0.0239 mole) of 0t,0t,0t',a'- tetrafluoroethylene-Z,2 bis (benzylhexaminium bromide), 25.6 ml. of concentrated hydrochloric acid and 135 ml.

of absolute ethanol is heated to refluxing for 9 hours. After cooling, the white precipitate is filtered and the :51- trate evaporated under reduced pressure. The residue and the precipitate are combined, dissolved in water, and the cooled solution is made strongly basic with 40% aqueous sodium hydroxide. The white solid product separates and is collected, washed with water and ether, and dried by evaporation of a solution in benzene; M.P. 96-97" C. An additional quantity of the product is recovered from the ethereal washings; M.P. 93-95 C. An analytical sample melts at 985-100 C. after sublimation in vacuo.

Analysis.-Calcd. for C H F N C, 61.53; H, 5.16; N, 8.97. Found: C, 61.15; H, 5.09; N, 8.83.

The (i) dilactate salt is prepared by treating a solution of a,a,a,a-tetrafiuoroethylene-2,2-bis (benzylamine) in isopropyl alcohol with a slight excess of -90% (:t) lactic acid. The (i) dilactate precipitates in white crystals, M.P. 180.5-181.5 C. Repeated recrystallization from absolute ethanol-absolute methanol yields a purified sample; M.P. 186 187.5 C.

AnaIysis.Calcd. for C16H16F4N2'2C3H603: C, H, 5.73; N, 5.69. Found: C, 53.92; H, 5.91; N, 5.69.

EXAMPLE 84 (A) 2',3-dimethyl 2 phenylacetophenone.--By following essentially the same procedures described in Example 1, 2,3-dimethylbenzonitrile is reacted with benzylmagnesium chloride to yield 2,3-dimethylphenylbenzyl ketimine hydrochloride. After recrystallization from absolute ethanol-absolute ether, the product is obtained as white crystals, M.P. 228.5-229.5 C.

Analysis.-Calcd. for C H N-HC1: C, 73.97; H, 6.98; N, 5.39. Found: C, 73.49; H, 6.89; N, 5.29.

Hydrolysis of the ketimine hydrochloride by essentially the same procedure described in Example 1 gives 2',3'- dimethyl-Z-phenylacetophenone. After recrystallizations from isopropyl alcohol and from methanol, the purified pgoduct is obtained as a white crystalline solid, MP. 52-- (B) 2,3-dimethylbenzil.-By following essentially the same procedures described in Example 2, 2',3'-dimethyl- Z-phenylacetophenone is oxidized to 2,3-dimethylbenzil. The crystalline product is purified by repeated recrystallization from absolute methanol; M.P. 61.562.5 C.

(C) 2,3 dimethyl 0t,0L,ot',ot' tetrafluorobibenzy1.-By following essentially the same procedures described in Example 83, 2,3-dimethylbenzil is converted to 2,3-dimethyl-a,a,a,a'-tetrafiuorobibenzyl. The crude crystalline product is purified by sublimation at C. and 0.05 mm.; M.P. 111.5 C. The analytical sample, M.P. 110- 111 C., is obtained by recrystallization from hexane.

Analysis.Calcd. for C H F C, 68.08; H, 5.00; F, 26.92. Found: C, 68.16; H, 5.16; F, 26.63.

(D) 3-(a,u,fl,p-tetrafiuorophenethyl) 0 xylene-u,a'- dibromide.-A mixture of 6.13 g. (0.022 mole) of 2,3- dimethyl-u,a,a',a'-tetrafiuorobibenzyl, 7.85 g. (0.044 mole) of N-bromosuccinimide, a catalytic amount of benzoyl peroxide, and ml. of carbon tetrachloride is stirred at reflux for 6 hours. After cooling, the precipitate of succinimide is filtered and washed with carbon tetrachloride. Evaporation of the filtrate under reduced pressure leaves the product as a slightly oily while solid, M.P. 71 83 C. Recrystallization from petroleum ether yields purified material, M.P. 8892 C. A sample for analysis is sublimed at 85 C. and 0.02 mm.; M.P. 90-92" C.

Analysis.-Calcd. for C H Br 'F C, 43.66; H, 2.75. Found: C, 43.78; H, 2.74.

(E) N,N-dimethyl 3 (a,0 3,fl-tetrafluorophenethyl)- o-xylene 1:,11' diamine.-3-(u,u,.fi,/3-tetrafluorophenethyl)-o-xylene-a,a-dibromide, 2.0 g. (0.0045 mole), is added to about 15-25 ml. of liquid methylamine cooled in a Dry Ice-chloroform bath. The solid dissolves and 27 after minutes, the cooling bath is removed and the solution is allowed to evaporate. The residual solid is triturated with benzene and the insoluble methylamine hydrobromide is removed by filtration. Evaporation of the benzene filtrate under reduced pressure leaves the product as the residual gummy solid.

The base is converted to the dihydrobromide salt by introducing gaseous hydrogen bromide into an ethanolic solution. Dilution with absolute ether precipitates the dihydrobromide that is recrystallized from absolute ethanolabsolute ether to obtain purified material, M.P. 254256 C. A sample for analysis melts at 251-253 C. after recrystallization from absolute ethanol.

Analysis.-Calcd. for C H F N '2HBr: C, 43.04; H, 4.41; N, 5.58; Br, 31.83. Found: C, 43.21; H, 4.39; N, 5.60; Br, 31.64.

EXAMPLE 85 A solution of 2.2 g. (0.005 mole) of 3-(a,a,,8,B-tetrafiuorophenethyl) o xylene-u,a'-dibromide and 1.7 g. (0.016 mole) of benzylamine in 50 ml. of dry benzene is stirred at room temperature for minutes. During this period, a white precipitate begins to separate; the mixture is heated to refluxing for 18 hours. After cooling, the precipitate of benzylamine hydrobromide is collected and washed with benzene. Evaporation of the benzene filtrate leaves a viscous yellow oil as the residue that is triturated with boiling absolute ether. The insoluble hydrobromide salt of the product is collected and recrystallized from benzene-absolute ethanol-absolute ether to obtain white crystalline solid, M.P. l72174 C. Recrystallization from acetone aflords the analytical sample, M.P. 176177.5 C.

Analysis.Ca1cd. for C H F N -HBr: C, 62.81; H, 5.10; N, 4.89. Found: C, 62.64; H, 5.10; N, 5.22.

EXAMPLE 86 4-(a,a,5,5-tetrafluorophenethyl)-isoindoline (A) N-benzyl 4 (a,a,fl,B-tetrafluorophenethyl)-isoindoline.The ethereal filtrate remaining after collection of N,N,-dibenzyl 3 (a,a,p,B-tetrafluorophenethyl)-oxylene-a,a-diamine hydrobromide as described in Example 85 is evaporated to dryness in vacuo leaving the crude product as the viscous, oily yellow base. The hydrobromide salt is prepared by treating a methanolic solution of the base with an equivalent of 48% aqueous hydrobromic acid. Dilution with absolute ether precipitates the hydrobromide, M.P. 228231 C. A sample for analysis is obtained as white crystals, M.P. 236.5238.5 C., after repeated recrystallization from absolute methanolabsolute ether and treatment with decolorizing carbon.

Analysis.--Calcd. for C H F N-HBr: C, 59.24; H, 4.32; N, 3.00. Found: C, 58.84; H, 4.30; N, 3.05.

(B) 4-(a,a,,6,p tetrafiuorophenethyl) isoindoline.A solution of 1.63 g. (0.0035 mole) of N-benzyl-4-(ot,a,p,5-

tetralfluorophenethyl)-isoincloline hydrobromide in 160 ml.

absolute ethanol-14 ml. absolute methanol is stirred with 320 mg. of 5% palladium on carbon under hydrogen at atmospheric pressure until the absorption of hydrogen is complete. The catalyst is removed by filtration and evaporation of the filtrate under reduced pressure leaves the crystalline hydrobromide salt of the product, M.P. 191- 192 C., as the residue. Recrystallizations from absolute ethanol-absolute ether, with treatment with decolorizing carbon, and from isopropyl alcohol afford the analytical sample, M.P. 192-l94 C.

Analysis.-Calcd. for C H F N-HBr: C, 51.09; H, 3.75; N, 3.72. Found: C, 50.94; H, 3.78; N, 3.83.

EXAMPLE 87 2-methyl-3-(a,u,B, 3-tetrafluorophenethyl)-benz lamine (A) 2-methyl-3-(a,a,fl,fi-tetrafiuorophenethyl) benzyl bromide-A mixture of 4.0 g. (0.0142 mole) of 2,3-di- 28 methyl-ct,a,a,ddetrafiuorobibenzyl, 2.52 g. (0.0142 mole) of N-bromosuccinimide, about 50 mg. of benzoyl peroxide, and 100 ml. of carbon tetrachloride is stirred at reflux for 2% hours. After cooling, the precipitate of succinimide is removed by filtration and the filtrate is evaporated to dryness under reduced pressure. The residual solid is recrystallized from petroleum ether to yield the white crystalline product, M.P. 6771 C. Repeated recrystallization from petroleum ether affords the analytical sample, M.P. 69-71 C.

Analysis.Calcd. for C H BrF C, 53.211; H, 3.63; Br, 22.12. Found: C, 54.21; H, 3.84; Br, 21.38. V

(B) N-[2-methyl-3 (a,oc,fl,fl tetrafiuorophenethyl)- benzyl]-phthalimide.A mixture of 8.02 g. (0.022 mole) of 2-methyl-3-(m /3,5-tetrafiuorophenethyl)-benzyl bromide, 4.10 g. (0.022 mole) of potassium phthalimide, and 40 ml. of dimethylforrnarnide is stirred 30 minutes at room temperature, 4 hours at C., and 3 hours at reflux. The cooled mixture is diluted with ml. of chloroform and washed with 150 ml. of water. After re-extraction of the aqueous layer with chloroform, the combined organic extracts are washed with 0.1 N sodium hydroxide, water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. Recrystallization of the residual solid from isopropyl alcohol affords the white crystalline product, MJP. 137 C.

(C) 2-methyl-3 a,oufi,fl-tetrafiuorophenethyl) -benzylamine.N-[2-methyl-3 (a,a,,8,fi tetrafluorophenethyl)- benzyl]-phthalimide, 3.74 g. (0.00876 mole), is dissolved in 100 ml. of boiling 95% ethanol. Hydrazine hydrate, 0.87 ml. of 100%, is added and the mixture is heated to refluxing for 7 hours. Upon cooling and standing, a voluminous white precipitate of phthalhydrazide separates and is removed by filtration. Evaporation of the ethanolic filtrate to approximately one-half volume yields additional precipitate of phthalhydrazide that is removed by filtration. The filtrate then is cooled in an ice-bath, acidified to pH 2 with about 1.5 ml. of concentrated hydrochloric acid, and evaporated to dryness under reduced pressure. The residual solid is dissolved in 25 ml. of absolute ethanol. Dilution of the solution with about 15 ml. of absolute ether yields additional precipitate of phthalhydrazide that is filtered. Concentration of the filtrate to a volume of about 15 ml. and dilution with 25 ml. of absolute ether precipitates the hydrochloride salt of the product as shiny white plates, M.P. 199.5-201" C. Repeated recrystallizations from absolute ethanol-absolute ether afford the purified hydrochloride, M.P. 209211.5 C.

Analysis.-Calcd. for C H F N-HCl: C, 57.58; H, 4.83; N, 4.20. Found: C, 57.28; H, 4.83; N, 4.12.

EXAMPLE 88 a,a-Dimethyl-3- a,oc, 5,5-tetrafiuorophenethyl) benzylamine (A) 3-br0rno-2-phenylacetophenone.-By following essentially the same procedures described in Example 1, 3- bromobenzonitrile is reacted with benzylmagnesiurn chloride to yield 3-bromophenyl benzyl ketimine hydrochloride. This salt is obtained as an oily solid that is hydrolyzed directly without purification by essentially the same procedure described in Example 1. The crude 3-bromo-2- phenylacetop-henone, an oily solid, is distilled in vacuo, collecting the pale yellow solid product over a range of 143l55 C./0.1 mm. The fraction boiling at -155 C./0.1 mm. is recrystallized from hexane to obtain the analytical sample as white crystals, M.P. 6264 C.

Analysis-Calcd. for C H BrO: C, 61.11; H, 4.03. Found: C, 61.25; H, 4.00.

(B) 3-bromobenzil.--By following essentially the same procedures described in Example 2, 3'-bromo-2-phenylacetophenone is oxidized to 3-bromobenzil.. The oily product is purified by vacuum distillation; B.P. l48155 C./ 0.05 mm. The distillate solidifies to yellow crystals, M.P.

78-82 C. and a sample for analysis is obtained by recrystallization from hexane; M.P. 81-82.5 C.

Analysis-Calcd. for C H BrO C, 58.15; H, 3.13. Found: C, 57.81; H, 3.05.

(C) 3-bromo-a,a,ot,a-tetrafluorobibenzyl.By following essentially the same procedures descdibed in Example 83, 3-bromobenzil is converted to 3-bromo-u,u,u',a-tetrafluorobibenzyl. The crude crystalline product is purified by sublimation at 65 C. and 0.02 mm; M.P. 72-75 C. The analytical sample, M.P. 74-76 C., is obtained by recrystallization from petroleum ether.

Analysis.-Calcd. for C H 'BrF C, 50.47; H, 2.72. Found: C, 50.51; H, 2.57.

(D) 2 [3 (a,et,fl,fi tetrafiuorophenethyl)-phenyl]- propanol-2.-The Grignard reagent, 3-(a,u,fi,/3-tetrafluorophenethyl)-phenylmagnesium bromide, is prepared as follows. In a nitrogen atmosphere, magnesium turnings, 0.72 g. (0.0297 g. atom), are covered with 6 ml. of absolute ether; a crystal of iodine is added and a few ml. of a solution of 8.97 g. (0.027 mole) of 3-bromo-u, x,ot',a'-

tetrafluorobibenzyl in 30 ml. of absolute ether are introduced. The mixture is stirred and heated to refluxing; a few drops of a solution of 0.2 g. of ethylene bromide in 1 ml. of absolute ether are added. Dropwise addition of the remaining solution of the bromide is begun and stirring at reflux is continued for several hours after the formation of the Grignard adduct is initiated. During this period, several additions of a total of 0.1 g. of freshly cut pieces of magnesium and the remainder of the ethylene bromide solution are made.

The solution of the Grignard reagent is cooled in an ice-bath and a solution of 3.5 g. (0.06 mole) of acetone in 5 ml. of absolute ether is added dropwise.

After stirring at room temperature and in a nitrogen atmosphere overnight, the mixture is cooled in an icebath and hydrolyzed by the dropwise addition of 2 ml. of water. The ethereal solution is decanted from the gelatinous precipitate that is re-extracted several times with ether. The combined, washed and dried, ethereal extracts are evaporated under reduced pressure, leaving the crude product as the residual solid. Purification is effected by column chromatography on 200 g. of silica gel, the product being eluted with benzene. The fractions which show one spot of Rf 0.2 on a silica thin layer plate developed with chloroform are combined. Evaporation of the solvent under reduced presure leaves the white crystalline product. A sample for analysis is recrystallized from hexane; M.P. 76-78 C.

Analysis.-Calcd. for C H F O: C, 65.37; H, 5.16. Found: C, 65.54; H, 5.15.

(E) N [at,a-dimethyl 3 (a,a,/3,B-tetrafiuorophenethyD-benzyl]-formamide.--Glacial acetic acid, 6 ml., is stirred and cooled in an ice-bath until it is half-solid; sodium cyanide, 1.08 g. (0.022 mole) is added in portions, keeping the temperature to 15-20 C. An ice-cold solution of 5.4 g. of concentrated sulfuric acid in 2.8 ml. of glacial acetic acid is added slowly, keeping the temperature at -20 C. After stirring for 10 minutes, the ice-bath is removed and a solution of 5.58 g. (0.01785 mole) of 2- [3-(a,a, 3, 3-tetrafluorophenethyl) phenyH-propanol-Z in 3 ml. of glacial acetic acid is introduced. Stirring is continued at 25 f C. for 9 hours. The reaction mixture is poured into about 80ml. of ice and water and neutralized by the addition of solid sodium carbonate. The oily product is extracted into ether. Evaporation of the washed and dried ethereal extract leaves the product as the residual oily solid. Purification is effected 'by column chromatography on 200 g. of silica gel, the product being eluted with chloroform. The fractions which show one spot of Rf 0.1 on a silica thin layer plate developed with chloroform are combined. Evaporation of the solvent under reduced pres- 30 [a,a-dirnethyl-3-(a,a,p,/3-tetrafluorophenethyl) benzylJ- formamide in 56 ml. glacial acetic acid-35 ml. Water-5.6 ml. concentrated hydrochloric acid is stirred at reflux for 6 hours. Evaporation of the solvents under reduced pressure leaves the hydrochloride salt of the product as the white crystalline residue. Recrystallization from absolute methanol-absolute ether affords the purified hydrochloride, M.P. l79-180 C. The melting point is unchanged by recrystallization from absolute methanolabsolute ether.

Analysis.-Calcd. for C H F,,N'HC1: C, 58.71; H, 5.22; N, 4.02. Found: C, 58.93; H, 5.58; N, 3.85.

EXAMPLE 89 4- oz, a,fl,fl-tetra-fluorophenethyl -benzylamine (A) 4-bromo-a,a,a',ot' tetrafluorobibenzyl.-By following essentially the same procedures described in Example 3, 4-bromobenzil is converted to 4bromo-a,u,a',ottetrafluorobibenzyl. The crude crystalline product is purified by sublimation at 70-75 C. and 0.02 mm.; M.P. 80- 82 C. A sample for analysis, M.P. 82-83.5 C., is obtained by resublimation.

Analysis.--Calcd. for C H BrF C. 50.49; H, 2.72; Br, 24.00. Found: C, 50.51; H, 2.81; Br, 23.78.

(B) 4-(oz,nt,fl,)9 tetrafiuorophenethyl) benzonitrile. By following essentially the same procedures described in Example 4, 4-bromo-u,a,a,ddetrafiuorobibenzyl is converted to 4-(a,a, 3,B-tetrafluorophenethyl) benzonitrile. The crude crystalline product is purified by sublimation at 85 C. and 0.02 mm.; M.P. 118-123 C. Resublimation affords almost white solid, M.P. 120.5-123 C. A sample for analysis is recrystallized from hexane and resublimed; M.P. 123.5-125.5 C.

Anwlysis.-Calcd. for C H F N: C, 64.52; H, 3.25; N, 5.02. Found: C, 64.76; H, 3.37; N, 4.80.

(C) 4-(a,u,fl,;8 tetrafluorophenethyl)-benzylamine.- By following essentially the same procedures described in Example 5, 4-(a,a,/3,B-tetrafluorophenethyl)-benzonitrile is reduced to 4-(a,a,fi, 9-tetrafluorophenethyl)-benzylamine. The white crystalline product, M.P. 995-102" C., is purified by sublimation at 90 C. and 0.01 mm.; M.P. 101-103 C.

Analysis.Calcd. for C H F N: C, 63.57; H, 4.62; N, 4.94. Found: C, 63.66; H, 4. 80; N, 4.97.

The base may be converted to the hydrochloride salt by treating a solution in ethanol with a slight excess of ethanolic hydrogen chloride. The hydrochloride separates in white flakes, M.P. 252-253 C. The melting point is unchanged by further recrystallization from ethanol.

Analysis.-Calcd. for C H F N-HCI: C, 56.35; H,

4.41; N, 4.38. Found: C, 56.37; H, 4.48; N, 4.35.

EXAMPLE a-Methyl-4- a,a,fl,ptetrafiuorophenethyl) -benzylamine (A) 4-(a,a,,B,B tetrafluorophenethyl-acetophenone.- A solution of 3.3 g. (0.0118 mole) of 4-(a,ot,/3,{3-tetrafluorophenethyl)-benzonitrile in 25 ml. of dry, peroxidefree tetrahydrofuran is added dropwise to a stirred solution of about 0.03 mole of methylmagnesium bromide in 25 ml. of absolute ether in a nitrogen atmosphere. The mixture is stirred at reflux for about 26 hours. After cooling in an ice-bath, the adduct is hydrolyzed by the dropwise addition of about 5 ml. of water and the mixture is diluted with about 50 ml. of ether. The organic phase is decanted and the gelatinous precipitate is washed thoroughly with ether. The combined ethereal extracts are washed once with water, extracted with 15 ml. of icecold 6 N hydrochloric acid in several portions, and then washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure leaves the product as the oily solid residue. Sublimation at -100 C. and 0.02 mm. gives purified material as white crystals, M.P. 128-133 C. A sample for anal- 31 ysis, M.P..134-135.5 C., is obtained by repeated recrystallization from hexane and resublimation.

AnalysiS.-Calcd. for C16H12F40: C, H,

F, 25.65. Found: C, 65.09; H, 4.31; F, 25.23.

' pressure and the residual solid is triturated with water.

The crystalline product, M.P. 137139 C., is collected and recrystallized from hexane to obtain white needles, M.P. 139-141 C. Recrystallization from hexane affords the analytical sample, M.P. 140-141 C.

Analysis.--Calcd. for C H F NO: C, 61.73; H, 4.21; N, 4.50. Found: C, 61.90; H, 4.20; N, 4.50.

(C) a-Methyl 4 (a,a,B,fl-tetrafiuorophenethyl)-benzylamine.--A solution of 2.45 g. (0.00787 mole) of 4'- (a,a,pLfi-tetrafiuorophenethyl)-acetophenone oxime in 47 ml. absolute ethanol-3 ml. 8 N hydrogen chloride in ethanol is stirred with 1.0 g. of 5% palladium on carbon under hydrogen at atmospheric pressure and 27 C. until the absorption of hydrogen is complete. The catalyst is removed by filtration and evaporation of the filtrate un-- der reduced pressure leaves a residual solid that is triturated with benzene and ether. The insoluble hydrochloride salt of the product is collected; M.P. 210-213 C. Repeated recrystallizations from ethanol-ether, acetone, and cold methanol-ether alford the purified hydrochloride, M.P. 216-217 C. The salt is suspended in water, the icecold mixture made strongly basic with 5% aqueous sodium hydroxide and the base extracted into benzene. Evaporation of the washed and dried benzene extract leaves the product as the residual white crystalline solid, M.P. 63.5-66 C. A sample for analysis is sublimed at 60 C. and 0.05 mm.; M.P. 64.5-66 C.

Analysis.-Calcd. for C H N C, 64.65; H, 5.09; N, 4.71. Found: C, 64.55; H, 5.07; N, 4.72.

The base may be reconverted to the hydrochloride salt by treating a solution in methanol with a slight excess of 8 N hydrogen chloride in ethanol. Dilution with absolute ether precipitates the white crystalline hydrochloride,

M.P. 2152l7 C. Recrystallization from methanol-ether affords the analytical sample, M.P. 218219 C.

Analysis.-Calcd. for C H F N-HCl: C, 57.58; H,

i 4.83; N, 4.20. Found: c, 57.22; H, 4.75; N, 4.15.

EXAMPLE 91 fected by column chromatography on silica gel, the produet being eluted with chloroform. The fractions that show one spot of Rf 0.25 on a fluorescent silica thin layer plate developed with chloroform are combined. Evaporation of the solvent under reduced pressure leaves the White crystalline product, M.P. 60-62" C. A sample for analysis is sublimed at 60 C. and 0.02 mm.; M.P. 62-635 C.

Analysis.Calcd. for C H F O: C, 65.37; H, 5.16; F, 24.33. Found: C, 65.46; H, 5.19; F, 24.52.

(B) 2- [4-( a,a,;8,p-tetrafluorophenethyl -phenyl] -propano1-2.--A solution of 500 mg. (0.00169 mole) of 4'- (u,c p,B-tetrafiuorophenethyl)-acetophenone in 18 ml. of absolute ether is added dropwise to a stirred solution of about 0.00189 mole of methylmagnesium bromide in 5 ml. of absolute ether at room temperature and in a nitrogen atmosphere. After 4 hours at reflux and an overnight period at room temperature, the mixture is cooled in an ice-bath and hydrolyzed by the dropwise addition of 4 ml. of water. After filtration, the ethereal layer is separated from the filtrate, washed with water, and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure leaves the crystalline product as the residue. Sublimation at 67 C. and 0.02 mm. gives purified material, M.P. 5460 C.

(C) N- u,ot-dimethyl-4- 11,04, 5, fi-tetrafluorophenethyl benzyl]-formamide.-By following essentially the same procedures described in Example 88, 2[4-(a,a,fl,fi-tetrafiuorophenethyl)-phenyl]-propanol-2 is converted via the Ritter reaction to N-[a, x-dimethyl-4-(a,a,fi,fl-tetrafiuoro phenethyl)-benzyl]-formamide. The crude oily solid mixture is separated by column chromatography on silica gel, the product being eluted with chloroform and 2% methanol in chloroform. The fractions that show one spot of Rf 0.17 on a fluorescent silica thin layer plate developed with chloroform are combined. Evaporation of the solvent under reduced pressure leaves the white crystalline product, M.P. 115.5-117 C. Recrystallization from absolute ether-petroleum ether affords the analytical sample, M. P. 116.5118 C.

Analysis.Calcd. for C H F NO: C, 63.71; H, 5.05; N, 4.13. Found: C, 63.96; H, 4.83; N, 4.01.

(D) 2 [4 (a,a, 3,;9-tetrafiuorophenethyl)-phenyl]propene.Column chromatography on silica gel of the crude oily solid mixture obtained from the Ritter reaction on 2-[4-(a,a,,8,,8-tetrafluorophenethyl)phenyl1-propanol-2 as described above in Example 91(C) affords 2-[4-(u,a,/i,[3- tetrafluorophenethyl)-phenyl]-propene as the second component. The fractions showing a major component at the solvent front on a fluorescent silica thin layer plate developed with chloroform are combined. Evaporation of the solvent under reduced pressure leaves the white crystalline product, M.P. 97-104 C. Sublimation at C. and 0.02 mm. affords a purified sample, M.P. 106.5111 C.

Analysis.Calcd. for C H F C, 69.38; H, 4.79. Found: C, 69.58; H, 4.83.

(E) N [u,a-dimethyl-4-(a,a,fi,B-tetrafiuorophenethyl)- benzyl]-formamide.By following essentially the same procedures described in Example 88, 2-[4-(a,a,/3,fl-tetrafiuorophenethyl)-phenyl]-propene is converted via the Ritter reaction to N-[u,u-dimethyl-4-(a,a,/3,fi-tetrafiuorophenethyl) benzyl] formamide. The purified product, M.P. 115-119 C., is obtained by column chromatography on silica gel of the crude material as described above in Example 91(C).

(F) a,a-Dimethyl-4-(a,u,/3,,8-tetrafluorophenethyl)-benzylamine.-By following essentially the same procedures described in Example 88, N-[a,a-dimethyl-4-(a,a,/8,,3-tetrafluorophenethyl)-benzyl]-formamide is hydrolyzed to a,a-dimethyl 4 (a,a,fl,fl-tetrafluorophenethyl)-benzyl- 55. amine. The hydrochloride salt of the product, M.P. 271.5-

272.5 C., is isolated. Repeated recrystallizations from absolute ethanol-absolute ether alford the purified hydrochloride, M.P. 274-275 C.

Analysis.Calcd. for C H F N-HCI: C, 58.71; H, 5.22; N, 4.02. Found: C, 58.55; H, 5.26; N, 4.09.

EXAMPLE 92 By following essentially the same procedures described in Example 6, N-[a,u-dimethyl-4-(u,a,/3,;3-tetrafluorophenethyl)-benzyl]-formamide is reduced to 4-(a,a,B,,6-tetrafiuorophenethyl)-a,a,N-trimethylbenzylamine. The crude base is converted to the dihydrogen citrate salt by treating a solution in isopropyl alcohol with a solution of a molar equivalent of citric acid in isopropyl alcohol. Dilution with absolute ether precipitates the dihydrogen citrate as white crystals, M.P. 169-170 C. dec. Recrystallization from absolute ethanol-absolute methanol gives a purified sample, M.P. 166-168 C.

Analysis.-Calcd. for C H F N-C H O C, 55.70; H, 5.26; N, 2.71. Found: C, 55.82; H, 5.23; N, 2.53.

The base may be purified by sublimation at 80 C. and 0.02 mm. to yield white crystals, M.P. 65-80 C. The purified base is converted to the hydrochloride salt by treating a solution in absolute ether with a slight excess of 8.2 N hydrogen chloride in ethanol. The hydrochloride, M.P. 203-205 C., precipitates. A sample for analysis, M.P. 206-208 C., is obtained by repeated recrystallization from ethanol.

Analysis.-Calcd. for C H F N-HCl: C, 59.76; H, 5.57; N, 3.87. Found: C, 59.92; H, 5.55; N, 3.68.

EXAMPLE 93 4- a,a-p,fi-tetrafluorophenethyl) -a,a,N,N-tetramethylbenzylamine A solution of 5.8 g. (0.0167 mole) of u,a-dimethyl-4- (a,a,fi,/3-tetrafluorophenethyl)-benzylamine hydrochloride in 8 ml. of 88% formic acid is treated with 3 g. (0.1 mole) of 37% formaldehyde and the stirred mixture is heated in an oil bath at 95 C. overnight. After the addition of 5 ml. of concentrated hydrochloric acid to the cooled mixture, the solution is evaporated to dryness under reduced pressure. The residual syrup is dissolved in 120 ml. of water and the solution is rendered strongly alkaline with 40% aqueous sodium hydroxide. The base is extracted into benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the product as the residual oil; 6.7 g. This product is shown to contain unreacted starting material by thin layer chromatographic comparison to an authentic sample. The base is converted to the mixed hydrochloride salts by treating a solution in isopropyl alcohol with a slight excess of 8.2 N hydrogen chloride in ethanol. Dilution with ether precipitates the mixture of hydrochlorides, M.P. 182-l90 C. This material is combined with a similar mixture from a previous experiment and a solution of the 7.75 g. in 13.3 ml. of 88% formic acid is treated with 5.3 g. of 37% formaldehyde. The stirred mixture is heated in an oil bath at 95 C. for about 2 /2 days. Work-up by the procedure described above affords the oily base that is converted to the hydrochloride salt by the procedure described above to yield white crystals, M.P. 17l-173.5 C. Recrystallization from isopropyl alcohol gives the analytical sample, M.P. 174-175.5 C.

Analysis.-Calcd. for C H F N-HCl: C, 60.72; H, 5.90; N, 3.72 Found: C, 60.90; H, 5.75; N, 3.84.

EXAMPLE 94 4- (p-methyl-a,u,;8,5-tetrafluorophenethyl) a-N-trimethylbenzylamine (A) 4-bromo4'-methylbenzoin.-A solution of 67 g. (0.314 mole) of p-bromophenylglyoxal in 300 ml. of dry toluene is added dropwise over 1%. hours to a stirred suspension of 84 g. (0.6 mole) of anhydrous aluminum chloride in 1.25 l. of dry toluene cooled in an ice-bath. Stirring in the cold is continued for 5 hours and the mixture then is held at 5-10 C. overnight. The mixture is poured into about 2 l. of ice and 6 N hydrochloric acid. The aqueous phase is separated and re-extracted with three portions of benzene. The combined, washed and dried organic extracts are concentrated under reduced pressure to a volume of about 200 ml. Dilution with 150 ml. of petroleum ether precipitates the white crystalline product, M.P. 8082 C. Repeated recrystallization from 60% ethanol affords the analytical sample, M.P. 82-83.5 C.

Analysis.-Ca1cd. for C H BrO C, 59.02; H, 4.29. Found: C, 59.18; H, 4.27.

(B) 4-bromo-4-methylbenzil.-Cupric sulfate, 90 g. (0.36 mole), is stirred and heated on the steam-bath with 110 ml. of pyridine and 45 ml. of water until complete solution is obtained. 4-bromo-4-methylbenzoin, 55 g. (0.18 mole), is added and the mixture is stirred and heated on the steam-bath for 3 hours. During this period, the yellow crystalline product separates. After cooling and dilution with water, the product is collected, washed with water, 1 N hydrochloric acid, and water, and dried; M.P. 132-135 C. The analytical sample is obtained as yellow needles, M.P. l36-137 C., after repeated recrystallizations from 95% ethanol.

Analysis.-Calcd. for C H BrO C, 59.41; H, 3.66. Found: C, 59.49; H, 3.59.

(C) 4-bromo 4' methyl-a,m,a',ot-tetrafluorobibenzyl.By following essentially the same procedures described in Example 83, 4-bromo-4'-methylbenzil is converted to 4-bromo-4'-methyl-u,a,u',a-tetrafluorobibenzil. The crude crystalline product is purified by sublimation at C. and 0.05 mm.; white crystals, M.P. 103.5- 105.5 C. A sample for analysis is resublimed.

Analysis.--Calcd. for C H BrF C, 51.88; H, 3.19; Br, 23.01. Found: C, 51.87; H, 3.18; Br, 23.14.

(D) 2-[4-(p-methyl a,a,;8,fi tetrafluorophenethyl)- phenyl]-propanol-2.By following essentially the same procedures described in Example 88, 4-(pmethyl-u,a,}3,;8- tetrafluorophenethyl)-phenyl-magnesium bromide is prepared from 4-bromo-4-methyl-a,m,ot,a-tetrafluorobibenzyl and reacted with acetone to yield 2-[4-(p-methyla,a,{3,fl-tetrafluorophenethyl)-phenyl]-propanol 2. Purification of the crude oily solid product is eflected by column chromatography on silica gel, the product being eluted with chloroform. The fractions that show one spot of Rf 0.25 on a fluorescent silica thin layer plate developed with chloroform are combined. Evaporation of the solvent under reduced pressure leaves the pale yellow solid product, M.P. 83-88 C. A sample for analysis is obtained as white crystals, M.P. 88-90 C., by sublimation at 80 C. and 0.05 mm. and recrystallization from petroleum ether.

Analysis.-Calcd. for C H F 0: C, 66.25; H, 5.56; F, 23.29. Found: C, 66.18; H, 5.50; F, 23.33.

(E) N-[a,a-dimethyl-4-(p-methyl-a,a,,3,,8 tetrafiuorophenethyl)-benzy1]-formamide.-By following essentially the same procedures described in Example 88, 2-[4-(pmethyl-a,a,pgfl-tetrafluorophenethyl)-phenyl] propanol- 2 is converted via the Rider reaction to N-[u,a-dimethyl- 4-(p-methyl a,u, 9,f3 tetrafluorophenethyl) benzyl]- formamide. The crude solid mixture is separated by column chromatography on silica gel, the product being eluted with chloroform and 2% methanol in chloroform. The fractions showing one major spot at Rf 0.15 on a fluorescent silica thin layer plate developed with chloroform are combined. Evaporation of solvent under reduced pressure leaves the pale yellow crystalline product, M.P. l09-119 C. A sample for analysis, M.P. 121-1225 0., is obtained by recrystallizations from ethanol-water and ether-petroleum ether.

Analysis.--Calcd. for C H F NO: C, 64.58; H, 5.42; N, 3.96. Found: C, 64.34; H, 5.35; N, 3.76.

(F) 4-(p-methyl-u,a, 8,/8 tetrafluorophenethyl) a,a, N-trimethylbenzylamine-By following essentially the same procedures described in Example 6, N-[a,a-dimethyl-4-(p-methyl-a,a,;8,/3 tetrafluorophenethyl) -ben- ZyIJ-formamide is reduced to 4-(p-methyl-a,a,p,fi tetrafluOI'OphCIlCthYl)-a,a,N-tlilllfithYlbCllZYlfil'lllIlB. The crude oily base is converted to the hydrochloride salt by treating a solution in ethanol with a slight excess of 8 N hydrogen chloride in ethanol. Dilution with absolute ether precipitates the white crystalline hydrochloride, M.P. 189- 190 C. The melting point is unchanged by recrystallization from isopropyl alcohol-ether.

Analysis.--Calcd. for C19H21F4NHC1: C, 60.72; H, 5.90; N, 3.73. Found: C, 61.12; H, 5.81; N, 3.61.

EXAMPLE a,a-Dimethyl-4-(p-methyl-a,a,fl,p-tetrafiuorophenethyl)- benzylamine By following essentially the same procedures described in Example 88, N-[u,a-dimethyl-4-(p methyl a,a,fi,;3-

tetrafluorophenethyl)-benzyl] -formamide is hydrolyzed to a,a-dimethyl-4-(p methyl a,a,B,B tetrafiuorophenethyl)-benzylamine. The hydrochloride salt of the prod- 35 net, M.P. 254.5-256.5 C., is isolated. Recrystallization from absolute ethanol aifords a purified sample, M.P. 256-258 C.

Analysis.--Calcd. for C18H19F4N'HC1: C, 59.75; H, 5.57; N, 3.87. Found: C, 59.70; H, 5.59; N, 3.90.

36 160 g. of organic strong acid cation exchanger in the hydrogen form (also known as Rexyn 101(H)). The coloumn was eluted with water until the eluant, a total of 400 ml., was approximately at pH 5.5. The eluant was concentrated in vacuo to a volume of about 50 ml. and

the concentration of isethionic acid in the solution was EXAMPLE 96 determined by potentiometric titration to be 3.8 M. 2-amino-4-methyl-N-[2-(o e,p,p-tetrafiuorophenethyl)- 04,0: Dimethyl 4 (a,a,fi,fi tetrafiuorophenethyD- benzyl1-valeramide benzylamine, 4.1 g. (0.0132 mole), was dissolved in 20 l. of isopropyl alcohol and the solution treated with 3.7 In a nitrogen atmosphere, 3.7 g. (0.0146 mole) of 10 m Woodwards K reagent is stirred in 25 ml. of freshly dis- M lsethlom? geld .Crystamzanon of the tilled dry acetonitrile and the mixture is cooled to isethionate started after dilution with 400 ml. of absolute C inan ice salt bath A solution of 3 9 0146 mole) ether. The product was collected after several hours at ofN caIbobenZoXy I; 1eucine and 1 01'46 mole) of room temperature, washed with absolute ether, and dis triethylamine in 40 ml. of acetonitrile is added dropwise 15 5 1 2 s i was gig g at a rate such that the temperature remains at 5 to 0 twp 10a mg l m o 6 PFC Pct C The mixture is Stirmd for 55 min below C and was precipitated from the residual solution by dilution with 200 ml. of absolute ether; 5.8 g., M.P. 134.5-136. 32 235 3 1 igi g ig ifiggfi' g g 5 Recrystallization from 50 ml. of isopropyl alcohol-200 mole) of 2-(a,a,fi,fl-tetrafluorophenethyl)-benzylamine in ggiggig ffgg g s g' C 5217. 12 ml. of acetonitrile is added dropwise. The mixture is H 5 3 7 51 g C stirred for 1 hour below 0 C., 3 hours at room temperaf Zriiifififi.22311331551333.ft iia ffiifrffii -,Y 3, data f f t under reduced pressure, the residual viscous, yellow oil g ii i (ua"efl tetr uorop enet y enzy is partitioned between methylene chloride and water made Solubility in 400 mg /ml slightly basic with a few drops of 40% aqueous sodium pH of 1% soluztio'n in H hydroxide. The methylene chloride extract is washed with (B) a Dimethyl 4- np-tetrafluorophenethynwater, 1 N hydrochloric acid, Water, and dried over anbenzylanline(+) 1 ,1 44,, a 5 hydrous sodium sulfate. Evaporation of the solvent under tetrafluorophegethyl) benzylamine hydrochloride, reduced pressure leaves the N-carbobenzoxy derivative of (0.0172 mole) was Suspended in Saturated sodium 1 ps ggl ign i f 6 6 g g f i hy gli b9 5 bobenzox d bonate and the base extracted into hexane. The combined 6 1 Y Y eTlVa' hexane extracts were washed thoroughly with water and tesoventunereue su et. .ot 't of 5% palladium-charcoal until the absorption of hydrocrystalline b {p p 32%;: re g e w 6 gen is complete. The catalyst is removed by filtration and A l i f th ba e (0.017 mole) in 25 ml. of evaporation of the solvent under reduced pressure leaves ton was treated with a solution of 1.85 g. (0.0175 the product as the residual pale yellow oil. The base is 40 mole) of 85-90% (i) lactic acid in 5 ml. of acetone. converted to t Y g ate salt y tfeatlllg a Crystallization of the lactate started slowly after dilution $321123: iancialbsghgtgsgtlhe gifitainzlsogtirczlili ofdaln texcessV 1%5 111111. of absolute ether. The products vlvgs 1follectetg er in lon' 1 a er ours at room emperature an ours o ether precipitates 2-amino-4-methyl-N-[2-(a,a,fi,fl tetracooling at about 0 C.; 6.5 g. (95%), M.P. 146-148. fluorophenethyl)-benzyl]-valeramide hydrogen fumarate Recrystallization from 30 ml. of acetone-125 ml. of as white crystals, M.P. 137l40 C. dec. Repeated recrysabsolute ether gave a first crop of 4.75 g., M.P. 146- tallization from methanol-ether afiords a purified sample, 148. M.P. 140.514l.5 C. dec. Analysis.-Calcd. for C H F N-C H O C, 59.84;

Analysis.-Ca1cd. for C21H24F4N2o'C4H4 O4: C, H: N, Found: C, H, 5'75. N; H, 5.51; N, 5.47. Found: C, 58.74; H, 5.50; N, 5.50. (C) Other salts of a,a-dimethyl-4-(a,a,;3,l9-tetrafluoro- EXAMPLE 97 phenethyl)-benzylamine.-A solution of the base 11,0:- dimethyl 4 (a,a,,9,;8 tetrafluorophenethyl)-benzyl- Salts of wg tafip amine dissolved in isopropyl alcohol was titrated with an enzy amine equivalent amount of the desired acid to form the salt (A) 11, 1 Dimethyl 4-(a 8,B-tetralluorophenethyl)- which precipitates from solution completely on addition ggilzeylaiiviinesetlgiongteldgasodiuig iseithionaeihfi g1. gian gqtflal volurlneii of ethfar. ('ilihedpr eliipittttteii salt is tlien s ss ve m. wa er an esouion I ere rom sou on an rie e o owing tale applied to a thoroughly washed column of approximately represents the salts prepared with physical constants:

Analysis Reagents and salts Meltling l Calculated Found Free base Acid reagent Salt (E g?) C H N C H N -Dim th 14- M I A xza,afig te3mfluo alelc a ig gr i t i i g ss 5: 5 5 53 215 15 161 59 01 4 95 3 28 59 43 5.10 3.20

rophenethyD- gen maleate. benzylamine. B .-d0 Citric mg-gggeltligglglgzfimggtfigagg- 165-166 54.87 5.01 2.78 54.87 5.15 2.58

it t C .-d0- Tartaric a,gif gtgggl ig, f fifigtxguoro- 1 -187 54. 66 5.02 3. 04 54. 60 5. 46 2.76

hydrogen tartrat D do Phosphorie--.. a,aftmgfihfi-g-(a flfi tenggug o- 251-253 53. 96 5. 46 3.70 53.51 5.21 3, 71

e gerf phohatz lgd ratg y 0 E dn Sulfuric a,gfii ig tggig gfi gigt figgw 209. 5-211.5 52.70 5.40 3.62 52.51 5.00 a. 52

t 111 dr t a F do Methane sulfonlc.- a,iDimeilfyl-t(a,a,B,B-tetrafluoro- 206. 5211.5 53. 06 5.20 3,44 53. 22 5,32 3,32

phenethyl) benzylamlne methane sulfonate.

1 Decayed.

37 What is claimed is: 1. A compound of the formula or the non-toxic acid addition salts thereof.

2. The isetheionic acid salt of the compound of claim 1.

3. The lactic acid salt of the compound of claim 1. 4. The methane sulfonic acid salt of the compound of claim 1.

5. The hydrochloride of the compound of claim 1. 6. A compound of the formula CFa-CFz- (3H: mil

i 38 7. 11,0; Dimethyl 3 (u,a,fl,}3 -tetrafiuorophenethyl)- benzylarnine.

References Cited UNITED STATES PATENTS 3,308,019 3/1967 Kopf et a1 260-5708 X 3,483,254 12/1969 Shen et a1. 260570.8 X 3,555,093 1/1971 LItalian 260-5708 ROBERT V. HINES, Primary Examiner US. Cl. X.R.

260-243 B, 247, 247.1, 247.2 R, 247.5 R, 248.5, 250 R, 251 Q, 268 H, 268 R, 293.57, 293.58, 293.59, 293.6, 293.61, 293.78, 304, 309.6, 326 S, 326 A, 326.1, 326.3, 326.5 L, 326.5 R, 326.85, 465 F, 465 G, 471 C, 482 R, 501.1, 515 A, 556 AR, 562 P, 56 6 R, 566 A, 570.8 R, 570.9, 591, 592, 612 R, 618 D, 649 F, 649 R, 665 G; 424-246, 248, 250, 251, 253, 263, 267, 274, 316, 321, 324, 330

UNITED STATES PATENT OFFICE CERTIFICATE OF (IQRRECTION Patent No. 3,8l2 l77 D d May 21, 1974 Inventofls) Edward L. Engelhardt and Marcia E. Christy It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In column 2, line 25, formula 2 should read (cFz) 1kg) (CH2)IE-N Signed and sealed this 18th day of March 1.975.

(SEAL) Attest:

C. MARSHALL DANN Commissioner of Patents and Trademarks RUTH C. MASON Attesting Officer 

